Method of treating psoriasis with anti-IL23 specific antibody

ABSTRACT

A method of treating psoriasis in a patient previously treated with and determined to be an inadequate responder to an IL-12/23p40 antibody by administering an IL-23 specific antibody, e.g., guselkumab, in a safe and effective amount and the patient achieves PASI75, PASI90, PASI100 or IGA 0 or 1 score as measured 16, 24, 32, 40 and 48 weeks after initial treatment.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 62/422,891, filed 16 Nov. 2016. The entire contents of theaforementioned application are incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

The present invention concerns methods for treating psoriasis with anantibody that binds the human IL-23 protein. In particular, it relatesto a method of administering an anti-IL-23 specific antibody andspecific pharmaceutical compositions of an antibody, e.g., guselkumab,which is safe and effective for patients suffering from psoriasis, inpatients who are inadequate responders to IL-12/23p40 antibody therapy.

BACKGROUND OF THE INVENTION

Interleukin (IL)-12 is a secreted heterodimeric cytokine comprised of 2disulfide-linked glycosylated protein subunits, designated p35 and p40for their approximate molecular weights. IL-12 is produced primarily byantigen-presenting cells and drives cell-mediated immunity by binding toa two-chain receptor complex that is expressed on the surface of T cellsor natural killer (NK) cells. The IL-12 receptor beta-1 (IL-12Rβ1) chainbinds to the p40 subunit of IL-12, providing the primary interactionbetween IL-12 and its receptor. However, it is IL-12p35 ligation of thesecond receptor chain, IL-12Rβ2, that confers intracellular signaling(e.g. STAT4 phosphorylation) and activation of the receptor-bearing cell(Presky et al, 1996). IL-12 signaling concurrent with antigenpresentation is thought to invoke T cell differentiation towards the Thelper 1 (Th1) phenotype, characterized by interferon gamma (IFNγ)production (Trinchieri, 2003). Th1 cells are believed to promoteimmunity to some intracellular pathogens, generate complement-fixingantibody isotypes, and contribute to tumor immunosurveillance. Thus,IL-12 is thought to be a significant component to host defense immunemechanisms.

It was discovered that the p40 protein subunit of IL-12 can alsoassociate with a separate protein subunit, designated p19, to form anovel cytokine, IL-23 (Oppman et al, 2000). IL-23 also signals through atwo-chain receptor complex. Since the p40 subunit is shared betweenIL-12 and IL-23, it follows that the IL-12Rβ1 chain is also sharedbetween IL-12 and IL-23. However, it is the IL-23p19 ligation of thesecond component of the IL-23 receptor complex, IL-23R, that confersIL-23 specific intracellular signaling (e.g., STAT3 phosphorylation) andsubsequent IL-17 production by T cells (Parham et al, 2002; Aggarwal etal. 2003). Recent studies have demonstrated that the biologicalfunctions of IL-23 are distinct from those of IL-12, despite thestructural similarity between the two cytokines (Langrish et al, 2005).

Abnormal regulation of IL-12 and Th1 cell populations has beenassociated with many immune-mediated diseases since neutralization ofIL-12 by antibodies is effective in treating animal models of psoriasis,multiple sclerosis (MS), rheumatoid arthritis, inflammatory boweldisease, insulin-dependent (type 1) diabetes mellitus, and uveitis(Leonard et al, 1995; Hong et al, 1999; Malfait et al, 1998; Davidson etal, 1998). However, since these studies targeted the shared p40 subunit,both IL-12 and IL-23 were neutralized in vivo. Therefore, it was unclearwhether IL-12 or IL-23 was mediating disease, or if both cytokinesneeded to be inhibited to achieve disease suppression. Recent studieshave confirmed through IL-23p19 deficient mice or specific antibodyneutralization of IL-23 that IL-23 inhibition can provide equivalentbenefit as anti-IL-12p40 strategies (Cua et al, 2003, Murphy et al,2003, Benson et al 2004). Therefore, there is increasing evidence forthe specific role of IL-23 in immune-mediated disease. Neutralization ofIL-23 without inhibition of IL-12 pathways could then provide effectivetherapy of immune-mediated disease with limited impact on important hostdefense immune mechanism. This would represent a significant improvementover current therapeutic options.

Psoriasis is a common, chronic immune-mediated skin disorder withsignificant co-morbidities, such as psoriatic arthritis (PsA),depression, cardiovascular disease, hypertension, obesity, diabetes,metabolic syndrome, and Crohn's disease. Plaque psoriasis is the mostcommon form of the disease and manifests in well demarcated erythematouslesions topped with white silver scales. Plaques are pruritic, painful,often disfiguring and disabling, and a significant proportion ofpsoriatic patients have plaques on hands/nails face, feet and genitalia.As such, psoriasis negatively impacts health-related quality of life(HRQoL) to a significant extent, including imposing physical andpsychosocial burdens that extend beyond the physical dermatologicalsymptoms and interfere with everyday activities. For example, psoriasisnegatively impacts familial, spousal, social, and work relationships,and is associated with a higher incidence of depression and increasedsuicidal tendencies.

Histologic characterization of psoriasis lesions reveals a thickenedepidermis resulting from aberrant keratinocyte proliferation anddifferentiation as well as dermal infiltration and co-localization ofCD3+ T lymphocytes and dendritic cells. While the etiology of psoriasisis not well defined, gene and protein analysis have shown that IL-12,IL-23 and their downstream molecules are over-expressed in psoriaticlesions, and some may correlate with psoriasis disease severity. Sometherapies used in the treatment of psoriasis modulate IL-12 and IL-23levels, which is speculated to contribute to their efficacy. Th1 andTh17 cells can produce effector cytokines that induce the production ofvasodilators, chemoattractants and expression of adhesion molecules onendothelial cells which in turn, promote monocyte and neutrophilrecruitment, T cell infiltration, neovascularization and keratinocyteactivation and hyperplasia. Activated keratinocytes can producechemoattractant factors that promote neutrophil, monocyte, T cell, anddendritic cell trafficking, thus establishing a cycle of inflammationand keratinocyte hyperproliferation.

Elucidation of the pathogenesis of psoriasis has led to effectivebiologic treatments targeting tumor necrosis factor-alpha (TNF-α), bothinterleukin (IL)-12 and IL-23 and, most recently, IL-17 as well as IL-23alone (including in Phase 1 and 2 clinical trials using guselkumab). TheIL-12/23 antibody ustekinumab has been approved in the United States,Europe, Japan and many other countries worldwide in the treatment ofmoderate-to-severe plaque psoriasis. Ustekinumab administered bysubcutaneous injection at weeks 0 and 4 and then once every 12 weeksexhibited rapid and sustained clinical response, as assessed by thePsoriasis Area and Severity Index, a validated efficacy tool forpsoriasis. A Phase 3 study comparing ustekinumab with etanercept, a TNFantagonist, demonstrated that the efficacy of ustekinumab was superiorto that of etanercept over a 12-week period in patients withmoderate-to-severe psoriasis. In addition, reported adverse events wererelatively mild, with the majority of events including susceptibility tomild infections such as nasopharyngitis and upper respiratory tractinfection. Rates of infection were not higher in ustekinumab-treatedpatients when compared with placebo-treated patients over 12 weeks oftherapy; nor were they increased in association with higher, relative tolower, ustekinumab doses. Also, rates of serious infections,cardiovascular events, injection site reactions, and malignancies werelow.

Guselkumab (also known as CNTO 1959) is a fully human IgG1 lambdamonoclonal antibody that binds to the p19 subunit of IL-23 and inhibitsthe intracellular and downstream signaling of IL-23, required forterminal differentiation of T helper (Th)17 cells.

SUMMARY OF THE INVENTION

The present invention concerns a method of treating psoriasis in apatient treated with an antibody to IL-12/23p40 (e.g., ustekinumab) anddetermined to be an inadequate responder to IL-12/23p40 antibodytreatment, comprising measuring whether a patient treated with anIL-12/23p40 antibody is an inadequate responder; determining that apatient is an inadequate responder to IL-12/23p40 antibody treatmentfrom the measuring step; and subcutaneously administering to the patientdetermined to be an inadequate responder to IL-12/23p40 antibodytreatment, an anti-IL-23 specific antibody (also referred to as IL-23p19antibody), e.g., guselkumab, to the patient, in a safe and effectiveamount.

In addition, the method of the invention comprises measuring whether apatient treated with an IL-12/23p40 antibody is an inadequate responderby measuring an IGA or PASI score in the patient and the patient isdetermined to be an inadequate responder to IL-12/23p40 antibodytreatment by an IGA score (or PGA score) of greater than or equal to 2or a PASI score improvement of less than 75% compared to baseline PASIscore prior to treatment. Alternatively, an inadequate responder toIL-12/23p40 antibody treatment is a patient whose psoriasis is notcleared or almost cleared with clear or almost cleared being a PGA/IGAscore of 0 or 1. In another aspect of the method of the invention, theantibody specific to IL-23 is administered in an initial dose, 4 weeksafter the initial dose and every 8 weeks after the dose at 4 weeks andthe patient is a responder to the antibody specific to IL-23 and isidentified as having a PASI75 or greater, PASI90 or greater, PASI100 orgreater or PGA 0 or 1 score or IGA improvement of at least 2 measured16, 20 or 28 weeks after initial treatment. In the method, the antibodyspecific to IL-23 (e.g., guselkumab) is administered subcutaneously andis safe and effective treating psoriasis at any area of a patient, andmay be administered to treat a specific area selected from the groupconsisting of scalp, nails, hands and feet, wherein the antibodyspecific to IL-23 is administered at a dose of between 25 mg and 200 mg;wherein the antibody specific to IL-23 is administered at a dose of 50mg or 100 mg.

In another aspect, the composition used in the method of the inventioncomprises a pharmaceutical composition comprising: an anti-IL-23specific antibody in an amount from about 1.0 μg/ml to about 1000 mg/ml,specifically at 50 mg or 100 mg. In a preferred embodiment theanti-IL-23 specific antibody is guselkumab at 100 mg/mL; 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 of the pharmaceuticalcomposition; wherein the diluent is water at standard state.

In another aspect of the invention the pharmaceutical compositioncomprises an isolated anti-IL23 specific antibody having the guselkumabCDR sequences comprising (i) the heavy chain CDR amino acid sequences ofSEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: 44; and (ii) the light chainCDR amino acid sequences of SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO:73 at 100 mg/mL; 7.9% (w/v) sucrose, 4.0 mM Histidine, 6.9 mML-Histidine monohydrochloride monohydrate; 0.053% (w/v) Polysorbate 80of the pharmaceutical composition; wherein the diluent is water atstandard state.

Another aspect of the method of the invention comprises administering apharmaceutical composition comprising an isolated anti-IL-23 specificantibody having the guselkumab heavy chain variable region amino acidsequence of SEQ ID NO: 106 and the guselkumab light chain variableregion amino acid sequence of SEQ ID NO: 116 at 100 mg/mL; 7.9% (w/v)sucrose, 4.0 mM Histidine, 6.9 mM L-Histidine monohydrochloridemonohydrate; 0.053% (w/v) Polysorbate 80 of the pharmaceuticalcomposition; wherein the diluent is water at standard state.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows a patient disposition from an adverse event (AE) flowchart.

FIGS. 2A-D show the proportions of randomized patients who achieved anIGA of 0 or 1 and ≥2-grade improvement relative to week 16 (FIG. 2A),PASI 75 (FIG. 2B), PASI 90 (FIG. 2C), and PASI 100 (FIG. 2D) responsefrom week 16 through week 52. IGA=Investigator's Global Assessment; PASI75/90/100, ≥75%/90%/100% improvement in measured Psoriasis Area andSeverity Index.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein the method of treatment of psoriasis comprisesadministering isolated, recombinant and/or synthetic anti-IL-23 specifichuman antibodies and diagnostic and therapeutic compositions, methodsand devices.

As used herein, an “anti-IL-23 specific antibody,” “anti-IL-23antibody,” “antibody portion,” or “antibody fragment” and/or “antibodyvariant” and the like include any protein or peptide containing moleculethat comprises at least a portion of an immunoglobulin molecule, such asbut not limited to, at least one complementarity determining region(CDR) of a heavy or light chain or a ligand binding portion thereof, aheavy chain or light chain variable region, a heavy chain or light chainconstant region, a framework region, or any portion thereof, or at leastone portion of an IL-23 receptor or binding protein, which can beincorporated into an antibody of the present invention. Such antibodyoptionally further affects a specific ligand, such as but not limitedto, where such antibody modulates, decreases, increases, antagonizes,agonizes, mitigates, alleviates, blocks, inhibits, abrogates and/orinterferes with at least one IL-23 activity or binding, or with IL-23receptor activity or binding, in vitro, in situ and/or in vivo. As anon-limiting example, a suitable anti-IL-23 antibody, specified portionor variant of the present invention can bind at least one IL-23molecule, or specified portions, variants or domains thereof. A suitableanti-IL-23 antibody, specified portion, or variant can also optionallyaffect at least one of IL-23 activity or function, such as but notlimited to, RNA, DNA or protein synthesis, IL-23 release, IL-23 receptorsignaling, membrane IL-23 cleavage, IL-23 activity, IL-23 productionand/or synthesis.

The term “antibody” is further intended to encompass antibodies,digestion fragments, specified portions and variants thereof, includingantibody mimetics or comprising portions of antibodies that mimic thestructure and/or function of an antibody or specified fragment orportion thereof, including single chain antibodies and fragmentsthereof. Functional fragments include antigen-binding fragments thatbind to a mammalian IL-23. For example, antibody fragments capable ofbinding to IL-23 or portions thereof, including, but not limited to, Fab(e.g., by papain digestion), Fab′ (e.g., by pepsin digestion and partialreduction) and F(ab′)₂ (e.g., by pepsin digestion), facb (e.g., byplasmin digestion), pFc′ (e.g., by pepsin or plasmin digestion), Fd(e.g., by pepsin digestion, partial reduction and reaggregation), Fv orscFv (e.g., by molecular biology techniques) fragments, are encompassedby the invention (see, e.g., Colligan, Immunology, supra).

Such fragments can be produced by enzymatic cleavage, synthetic orrecombinant techniques, as known in the art and/or as described herein.Antibodies can also be produced in a variety of truncated forms usingantibody genes in which one or more stop codons have been introducedupstream of the natural stop site. For example, a combination geneencoding a F(ab′)₂ heavy chain portion can be designed to include DNAsequences encoding the C_(H)1 domain and/or hinge region of the heavychain. The various portions of antibodies can be joined togetherchemically by conventional techniques, or can be prepared as acontiguous protein using genetic engineering techniques.

As used herein, the term “human antibody” refers to an antibody in whichsubstantially every part of the protein (e.g., CDR, framework, C_(L),C_(H) domains (e.g., C_(H)1, C_(H)2, C_(H)3), hinge, (V_(L), V_(H))) issubstantially non-immunogenic in humans, with only minor sequencechanges or variations. A “human antibody” may also be an antibody thatis derived from or closely matches human germline immunoglobulinsequences. Human antibodies may include amino acid residues not encodedby germline immunoglobulin sequences (e.g., mutations introduced byrandom or site-specific mutagenesis in vitro or by somatic mutation invivo). Often, this means that the human antibody is substantiallynon-immunogenic in humans. Human antibodies have been classified intogroupings based on their amino acid sequence similarities. Accordingly,using a sequence similarity search, an antibody with a similar linearsequence can be chosen as a template to create a human antibody.Similarly, antibodies designated primate (monkey, baboon, chimpanzee,etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like)and other mammals designate such species, sub-genus, genus, sub-family,and family specific antibodies. Further, chimeric antibodies can includeany combination of the above. Such changes or variations optionally andpreferably retain or reduce the immunogenicity in humans or otherspecies relative to non-modified antibodies. Thus, a human antibody isdistinct from a chimeric or humanized antibody.

It is pointed out that a human antibody can be produced by a non-humananimal or prokaryotic or eukaryotic cell that is capable of expressingfunctionally rearranged human immunoglobulin (e.g., heavy chain and/orlight chain) genes. Further, when a human antibody is a single chainantibody, it can comprise a linker peptide that is not found in nativehuman antibodies. For example, an Fv can comprise a linker peptide, suchas two to about eight glycine or other amino acid residues, whichconnects the variable region of the heavy chain and the variable regionof the light chain. Such linker peptides are considered to be of humanorigin.

Bispecific, heterospecific, heteroconjugate or similar antibodies canalso be used that are monoclonal, preferably, human or humanized,antibodies that have binding specificities for at least two differentantigens. In the present case, one of the binding specificities is forat least one IL-23 protein, the other one is for any other antigen.Methods for making bispecific antibodies are known in the art.Traditionally, the recombinant production of bispecific antibodies isbased on the co-expression of two immunoglobulin heavy chain-light chainpairs, where the two heavy chains have different specificities (Milsteinand Cuello, Nature 305:537 (1983)). Because of the random assortment ofimmunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of 10 different antibody molecules, of whichonly one has the correct bispecific structure. The purification of thecorrect molecule, which is usually done by affinity chromatographysteps, is rather cumbersome, and the product yields are low. Similarprocedures are disclosed, e.g., in WO 93/08829, U.S. Pat. Nos.6,210,668, 6,193,967, 6,132,992, 6,106,833, 6,060,285, 6,037,453,6,010,902, 5,989,530, 5,959,084, 5,959,083, 5,932,448, 5,833,985,5,821,333, 5,807,706, 5,643,759, 5,601,819, 5,582,996, 5,496,549,4,676,980, WO 91/00360, WO 92/00373, EP 03089, Traunecker et al., EMBOJ. 10:3655 (1991), Suresh et al., Methods in Enzymology 121:210 (1986),each entirely incorporated herein by reference.

Anti-IL-23 specific (also termed IL-23 specific antibodies) (orantibodies to IL-23) useful in the methods and compositions of thepresent invention can optionally be characterized by high affinitybinding to IL-23 and, optionally and preferably, having low toxicity. Inparticular, an antibody, specified fragment or variant of the invention,where the individual components, such as the variable region, constantregion and framework, individually and/or collectively, optionally andpreferably possess low immunogenicity, is useful in the presentinvention. The antibodies that can be used in the invention areoptionally characterized by their ability to treat patients for extendedperiods with measurable alleviation of symptoms and low and/oracceptable toxicity. Low or acceptable immunogenicity and/or highaffinity, as well as other suitable properties, can contribute to thetherapeutic results achieved. “Low immunogenicity” is defined herein asraising significant HAHA, HACA or HAMA responses in less than about 75%,or preferably less than about 50% of the patients treated and/or raisinglow titres in the patient treated (less than about 300, preferably lessthan about 100 measured with a double antigen enzyme immunoassay)(Elliott et al., Lancet 344:1125-1127 (1994), entirely incorporatedherein by reference). “Low immunogenicity” can also be defined as theincidence of titrable levels of antibodies to the anti-IL-23 antibody inpatients treated with anti-IL-23 antibody as occurring in less than 25%of patients treated, preferably, in less than 10% of patients treatedwith the recommended dose for the recommended course of therapy duringthe treatment period.

The terms “efficacy” and “effective” as used herein in the context of adose, dosage regimen, treatment or method refer to the effectiveness ofa particular dose, dosage or treatment regimen. Efficacy can be measuredbased on change in the course of the disease in response to an agent ofthe present invention. For example, an anti-IL23 specific antibody ofthe present invention (e.g., the anti-IL23 specific antibody guselkumab)is administered to a patient in an amount and for a time sufficient toinduce an improvement, preferably a sustained improvement, in at leastone indicator that reflects the severity of the disorder that is beingtreated. Various indicators that reflect the extent of the subject'sillness, disease or condition may be assessed for determining whetherthe amount and time of the treatment is sufficient. Such indicatorsinclude, for example, clinically recognized indicators of diseaseseverity, symptoms, or manifestations of the disorder in question. Thedegree of improvement generally is determined by a physician, who maymake this determination based on signs, symptoms, biopsies, or othertest results, and who may also employ questionnaires that areadministered to the subject, such as quality-of-life questionnairesdeveloped for a given disease. For example, an anti-IL23 specificantibody of the present invention may be administered to achieve animprovement in a patient's condition related to psoriasis. Improvementmay be indicated by an improvement in an index of disease activity, byamelioration of clinical symptoms or by any other measure of diseaseactivity. Several such indexes of disease are the Investigator's GlobalAssessment (IGA), Physician's Global Assessment (PGA) or Psoriasis Areaand Severity Index (PAST) PASI score. The IGA, PGA or PASI scores areestablished, validated disease activity indexes for psoriasis.Additional measures are scalp-specific IGA (ss-IGA), fingernailPhysician's Global Assessment (f-PGA), Nail Psoriasis Area and SeverityIndex (NAPSI), and PGA of the hands/feet (hf-PGA).

The term “safe,” as it relates to a dose, dosage regimen, treatment ormethod with an anti-IL23 specific antibody of the present invention(e.g., the anti-IL23 specific antibody guselkumab), refers to afavorable risk:benefit ratio with an acceptable frequency and/oracceptable severity of treatment-emergent adverse events (referred to asAEs or TEAEs) compared to the standard of care or to another comparatorbased on the stage of clinical trials, e.g., Phase 3 trials. An adverseevent is an untoward medical occurrence in a patient administered amedicinal product. In particular, safe as it relates to a dose, dosageregimen or treatment with an anti-IL23 specific antibody of the presentinvention refers to with an acceptable frequency and/or acceptableseverity of adverse events associated with administration of theantibody if attribution is considered to be possible, probable, or verylikely due to the use of the anti-IL23 specific antibody.

Utility

The isolated nucleic acids of the present invention can be used forproduction of at least one anti-IL-23 antibody or specified variantthereof, which can be used to measure or effect in an cell, tissue,organ or animal (including mammals and humans), to diagnose, monitor,modulate, treat, alleviate, help prevent the incidence of, or reduce thesymptoms of psoriasis.

Such a method can comprise administering an effective amount of acomposition or a pharmaceutical composition comprising at least oneanti-IL-23 antibody to a cell, tissue, organ, animal or patient in needof such modulation, treatment, alleviation, prevention, or reduction insymptoms, effects or mechanisms. The effective amount can comprise anamount of about 0.001 to 500 mg/kg per single (e.g., bolus), multiple orcontinuous administration, or to achieve a serum concentration of0.01-5000 μg/ml serum concentration per single, multiple, or continuousadministration, or any effective range or value therein, as done anddetermined using known methods, as described herein or known in therelevant arts.

Citations

All publications or patents cited herein, whether or not specificallydesignated, are entirely incorporated herein by reference as they showthe state of the art at the time of the present invention and/or toprovide description and enablement of the present invention.Publications refer to any scientific or patent publications, or anyother information available in any media format, including all recorded,electronic or printed formats. The following references are entirelyincorporated herein by reference: Ausubel, et al., ed., CurrentProtocols in Molecular Biology, John Wiley & Sons, Inc., NY, N.Y.(1987-2001); Sambrook, et al., Molecular Cloning: A Laboratory Manual,2^(nd) Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane,antibodies, a Laboratory Manual, Cold Spring Harbor, N.Y. (1989);Colligan, et al., eds., Current Protocols in Immunology, John Wiley &Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols inProtein Science, John Wiley & Sons, NY, N.Y., (1997-2001).

Antibodies of the Present Invention—Production and Generation

At least one anti-IL-23 antibody used in the method of the presentinvention can be optionally produced by a cell line, a mixed cell line,an immortalized cell or clonal population of immortalized cells, as wellknown in the art. See, e.g., Ausubel, et al., ed., Current Protocols inMolecular Biology, John Wiley & Sons, Inc., NY, N.Y. (1987-2001);Sambrook, et al., Molecular Cloning: A Laboratory Manual, 2^(nd)Edition, Cold Spring Harbor, N.Y. (1989); Harlow and Lane, antibodies, aLaboratory Manual, Cold Spring Harbor, N.Y. (1989); Colligan, et al.,eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY(1994-2001); Colligan et al., Current Protocols in Protein Science, JohnWiley & Sons, NY, N.Y., (1997-2001), each entirely incorporated hereinby reference.

A preferred anti-IL-23 antibody is guselkumab (also referred to asCNTO1959) having the heavy chain variable region amino acid sequence ofSEQ ID NO: 106 and the light chain variable region amino acid sequenceof SEQ ID NO: 116 and having the heavy chain CDR amino acid sequences ofSEQ ID NO: 5, SEQ ID NO: 20, and SEQ ID NO: 44; and the light chain CDRamino acid sequences of SEQ ID NO: 50, SEQ ID NO: 56, and SEQ ID NO: 73.Other anti-IL-23 antibodies have sequences listed herein and aredescribed in U.S. Pat. No. 7,935,344, the entire contents of which areincorporated herein by reference).

Human antibodies that are specific for human IL-23 proteins or fragmentsthereof can be raised against an appropriate immunogenic antigen, suchas an isolated IL-23 protein and/or a portion thereof (includingsynthetic molecules, such as synthetic peptides). Other specific orgeneral mammalian antibodies can be similarly raised. Preparation ofimmunogenic antigens, and monoclonal antibody production can beperformed using any suitable technique.

In one approach, a hybridoma is produced by fusing a suitable immortalcell line (e.g., a myeloma cell line, such as, but not limited to,Sp2/0, Sp2/0-AG14, NSO, NS1, NS2, AE-1, L.5, L243, P3X63Ag8.653, Sp2SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1,JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMALWA, NEURO2A, or the like, or heteromylomas, fusion products thereof, or any cellor fusion cell derived therefrom, or any other suitable cell line asknown in the art) (see, e.g., www.atcc.org, www.lifetech.com., and thelike), with antibody producing cells, such as, but not limited to,isolated or cloned spleen, peripheral blood, lymph, tonsil, or otherimmune or B cell containing cells, or any other cells expressing heavyor light chain constant or variable or framework or CDR sequences,either as endogenous or heterologous nucleic acid, as recombinant orendogenous, viral, bacterial, algal, prokaryotic, amphibian, insect,reptilian, fish, mammalian, rodent, equine, ovine, goat, sheep, primate,eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA,chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single, double or triplestranded, hybridized, and the like or any combination thereof. See,e.g., Ausubel, supra, and Colligan, Immunology, supra, chapter 2,entirely incorporated herein by reference.

Antibody producing cells can also be obtained from the peripheral bloodor, preferably, the spleen or lymph nodes, of humans or other suitableanimals that have been immunized with the antigen of interest. Any othersuitable host cell can also be used for expressing heterologous orendogenous nucleic acid encoding an antibody, specified fragment orvariant thereof, of the present invention. The fused cells (hybridomas)or recombinant cells can be isolated using selective culture conditionsor other suitable known methods, and cloned by limiting dilution or cellsorting, or other known methods. Cells which produce antibodies with thedesired specificity can be selected by a suitable assay (e.g., ELISA).

Other suitable methods of producing or isolating antibodies of therequisite specificity can be used, including, but not limited to,methods that select recombinant antibody from a peptide or proteinlibrary (e.g., but not limited to, a bacteriophage, ribosome,oligonucleotide, RNA, cDNA, or the like, display library; e.g., asavailable from Cambridge antibody Technologies, Cambridgeshire, UK;MorphoSys, Martinsreid/Planegg, DE; Biovation, Aberdeen, Scotland, UK;BioInvent, Lund, Sweden; Dyax Corp., Enzon, Affymax/Biosite; Xoma,Berkeley, Calif.; Ixsys. See, e.g., EP 368,684, PCT/GB91/01134;PCT/GB92/01755; PCT/GB92/002240; PCT/GB92/00883; PCT/GB93/00605; U.S.Ser. No. 08/350,260 (May 12, 1994); PCT/GB94/01422; PCT/GB94/02662;PCT/GB97/01835; (CAT/MRC); WO90/14443; WO90/14424; WO90/14430;PCT/US94/1234; WO92/18619; WO96/07754; (Scripps); WO96/13583, WO97/08320(MorphoSys); WO95/16027 (BioInvent); WO88/06630; WO90/3809 (Dyax); U.S.Pat. No. 4,704,692 (Enzon); PCT/US91/02989 (Affymax); WO89/06283; EP 371998; EP 550 400; (Xoma); EP 229 046; PCT/US91/07149 (Ixsys); orstochastically generated peptides or proteins—U.S. Pat. Nos. 5,723,323,5,763,192, 5,814,476, 5,817,483, 5,824,514, 5,976,862, WO 86/05803, EP590 689 (Ixsys, predecessor of Applied Molecular Evolution (AME), eachentirely incorporated herein by reference)) or that rely uponimmunization of transgenic animals (e.g., SCID mice, Nguyen et al.,Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit. Rev.Biotechnol. 16:95-118 (1996); Eren et al., Immunol. 93:154-161 (1998),each entirely incorporated by reference as well as related patents andapplications) that are capable of producing a repertoire of humanantibodies, as known in the art and/or as described herein. Suchtechniques, include, but are not limited to, ribosome display (Hanes etal., Proc. Natl. Acad. Sci. USA, 94:4937-4942 (May 1997); Hanes et al.,Proc. Natl. Acad. Sci. USA, 95:14130-14135 (November 1998)); single cellantibody producing technologies (e.g., selected lymphocyte antibodymethod (“SLAM”) (U.S. Pat. No. 5,627,052, Wen et al., J. Immunol.17:887-892 (1987); Babcook et al., Proc. Natl. Acad. Sci. USA93:7843-7848 (1996)); gel microdroplet and flow cytometry (Powell etal., Biotechnol. 8:333-337 (1990); One Cell Systems, Cambridge, Mass.;Gray et al., J. Imm. Meth. 182:155-163 (1995); Kenny et al.,Bio/Technol. 13:787-790 (1995)); B-cell selection (Steenbakkers et al.,Molec. Biol. Reports 19:125-134 (1994); Jonak et al., Progress Biotech,Vol. 5, In Vitro Immunization in Hybridoma Technology, Borrebaeck, ed.,Elsevier Science Publishers B.V., Amsterdam, Netherlands (1988)).

Methods for engineering or humanizing non-human or human antibodies canalso be used and are well known in the art. Generally, a humanized orengineered antibody has one or more amino acid residues from a sourcethat is non-human, e.g., but not limited to, mouse, rat, rabbit,non-human primate or other mammal. These non-human amino acid residuesare replaced by residues often referred to as “import” residues, whichare typically taken from an “import” variable, constant or other domainof a known human sequence.

Known human Ig sequences are disclosed, e.g.,www.ncbi.nlm.nih.gov/entrez/query.fcgi; www.ncbi.nih.gov/igblast;www.atcc.org/phage/hdb.html; www.mrc-cpe.cam.ac.uk/ALIGNMENTS.php;www.kabatdatabase.com/top.html; ftp.ncbi.nih.gov/repository/kabat;www.sciquest.com; www.abcam.com;www.antibodyresource.com/onlinecomp.html;www.public.iastate.edu/˜pedro/research_tools.html;www.whfreeman.com/immunology/CH05/kuby05.htm;www.hhmi.org/grants/lectures/1996/vlab;www.path.cam.ac.uk/˜mrc7/mikeimages.html;mcb.harvard.edu/BioLinks/Immunology.html; www.immunologylink.com;pathbox.wustl.edu/˜hcenter/index.html; www.appliedbiosystems.com;www.nal.usda.gov/awic/pubs/antibody;www.m.ehime-u.ac.jp/˜yasuhito/Elisa.html; www.biodesign.com;www.cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net.org;baserv.uci.kun.nl/˜jraats/links1.html;www.recab.uni-hd.de/immuno.bme.nwu.edu; www.mrc-cpe.cam.ac.uk;www.ibt.unam.mx/vir/V_mice.html; http://www.bioinforg.uk/abs;antibody.bath.ac.uk; www.unizh.ch; www.cryst.bbk.ac.uk/˜ubcg07s;www.nimr.mrc.ac.uk/CC/ccaewg/ccaewg.html;www.path.cam.ac.uk/˜mrc7/humanisation/TAHHP.html;www.ibt.unam.mx/vir/structure/stat_aim.html;www.biosci.missouri.edu/smithgp/index.html; www.jerini.de; Kabat et al.,Sequences of Proteins of Immunological Interest, U.S. Dept. Health(1983), each entirely incorporated herein by reference.

Such imported sequences can be used to reduce immunogenicity or reduce,enhance or modify binding, affinity, on-rate, off-rate, avidity,specificity, half-life, or any other suitable characteristic, as knownin the art. In general, the CDR residues are directly and mostsubstantially involved in influencing antigen binding. Accordingly, partor all of the non-human or human CDR sequences are maintained while thenon-human sequences of the variable and constant regions may be replacedwith human or other amino acids.

Antibodies can also optionally be humanized or human antibodiesengineered with retention of high affinity for the antigen and otherfavorable biological properties. To achieve this goal, humanized (orhuman) antibodies can be optionally prepared by a process of analysis ofthe parental sequences and various conceptual humanized products usingthree-dimensional models of the parental and humanized sequences.Three-dimensional immunoglobulin models are commonly available and arefamiliar to those skilled in the art. Computer programs are availablewhich illustrate and display probable three-dimensional conformationalstructures of selected candidate immunoglobulin sequences. Inspection ofthese displays permits analysis of the likely role of the residues inthe functioning of the candidate immunoglobulin sequence, i.e., theanalysis of residues that influence the ability of the candidateimmunoglobulin to bind its antigen. In this way, framework (FR) residuescan be selected and combined from the consensus and import sequences sothat the desired antibody characteristic, such as increased affinity forthe target antigen(s), is achieved.

In addition, the human IL-23 specific antibody used in the method of thepresent invention may comprise a human germline light chain framework.In particular embodiments, the light chain germline sequence is selectedfrom human VK sequences including, but not limited to, A1, A10, A11,A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1,L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25,L4/18a, L5, L6, L8, L9, O1, O11, O12, O14, O18, O2, O4, and O8. Incertain embodiments, this light chain human germline framework isselected from V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-2, V1-20,V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-14, V2-15,V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3,V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6.

In other embodiments, the human IL-23 specific antibody used in themethod of the present invention may comprise a human germline heavychain framework. In particular embodiments, this heavy chain humangermline framework is selected from VH1-18, VH1-2, VH1-24, VH1-3,VH1-45, VH1-46, VH1-58, VH1-69, VH1-8, VH2-26, VH2-5, VH2-70, VH3-11,VH3-13, VH3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35,VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72,VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59,VH4-61, VH5-51, VH6-1, and VH7-81.

In particular embodiments, the light chain variable region and/or heavychain variable region comprises a framework region or at least a portionof a framework region (e.g., containing 2 or 3 subregions, such as FR2and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 isfully human. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 isfully human. In some embodiments, at least FRL1, FRL2, FRL3, or FRL4 isa germline sequence (e.g., human germline) or comprises human consensussequences for the particular framework (readily available at the sourcesof known human Ig sequences described above). In other embodiments, atleast FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., humangermline) or comprises human consensus sequences for the particularframework. In preferred embodiments, the framework region is a fullyhuman framework region.

Humanization or engineering of antibodies of the present invention canbe performed using any known method, such as but not limited to thosedescribed in, Winter (Jones et al., Nature 321:522 (1986); Riechmann etal., Nature 332:323 (1988); Verhoeyen et al., Science 239:1534 (1988)),Sims et al., J. Immunol. 151: 2296 (1993); Chothia and Lesk, J. Mol.Biol. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A.89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), U.S. Pat.Nos.: 5,723,323, 5,976,862, 5,824,514, 5,817,483, 5,814,476, 5,763,192,5,723,323, 5,766,886, 5,714,352, 6,204,023, 6,180,370, 5,693,762,5,530,101, 5,585,089, 5,225,539; 4,816,567, PCT/: US98/16280,US96/18978, US91/09630, US91/05939, US94/01234, GB89/01334, GB91/01134,GB92/01755; WO90/14443, WO90/14424, WO90/14430, EP 229246, each entirelyincorporated herein by reference, included references cited therein.

In certain embodiments, the antibody comprises an altered (e.g.,mutated) Fc region. For example, in some embodiments, the Fc region hasbeen altered to reduce or enhance the effector functions of theantibody. In some embodiments, the Fc region is an isotype selected fromIgM, IgA, IgG, IgE, or other isotype. Alternatively or additionally, itmay be useful to combine amino acid modifications with one or morefurther amino acid modifications that alter C1q binding and/or thecomplement dependent cytotoxicity function of the Fc region of an IL-23binding molecule. The starting polypeptide of particular interest may beone that binds to C1q and displays complement dependent cytotoxicity(CDC). Polypeptides with pre-existing C1q binding activity, optionallyfurther having the ability to mediate CDC may be modified such that oneor both of these activities are enhanced. Amino acid modifications thatalter C1q and/or modify its complement dependent cytotoxicity functionare described, for example, in WO0042072, which is hereby incorporatedby reference.

As disclosed above, one can design an Fc region of the human IL-23specific antibody of the present invention with altered effectorfunction, e.g., by modifying C1q binding and/or FcγR binding and therebychanging complement dependent cytotoxicity (CDC) activity and/orantibody-dependent cell-mediated cytotoxicity (ADCC) activity. “Effectorfunctions” are responsible for activating or diminishing a biologicalactivity (e.g., in a subject). Examples of effector functions include,but are not limited to: C1q binding; CDC; Fc receptor binding; ADCC;phagocytosis; down regulation of cell surface receptors (e.g., B cellreceptor; BCR), etc. Such effector functions may require the Fc regionto be combined with a binding domain (e.g., an antibody variable domain)and can be assessed using various assays (e.g., Fc binding assays, ADCCassays, CDC assays, etc.).

For example, one can generate a variant Fc region of the human IL-23 (oranti-IL-23) antibody with improved C1q binding and improved FcγRIIIbinding (e.g., having both improved ADCC activity and improved CDCactivity). Alternatively, if it is desired that effector function bereduced or ablated, a variant Fc region can be engineered with reducedCDC activity and/or reduced ADCC activity. In other embodiments, onlyone of these activities may be increased, and, optionally, also theother activity reduced (e.g., to generate an Fc region variant withimproved ADCC activity, but reduced CDC activity and vice versa).

Fc mutations can also be introduced in engineer to alter theirinteraction with the neonatal Fc receptor (FcRn) and improve theirpharmacokinetic properties. A collection of human Fc variants withimproved binding to the FcRn have been described (Shields et al.,(2001). High resolution mapping of the binding site on human IgG1 forFcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants withimproved binding to the FcγR, J. Biol. Chem. 276:6591-6604).

Another type of amino acid substitution serves to alter theglycosylation pattern of the Fc region of the human IL-23 specificantibody. Glycosylation of an Fc region is typically either N-linked orO-linked. N-linked refers to the attachment of the carbohydrate moietyto the side chain of an asparagine residue. O-linked glycosylationrefers to the attachment of one of the sugars N-aceylgalactosamine,galactose, or xylose to a hydroxyamino acid, most commonly serine orthreonine, although 5-hydroxyproline or 5-hydroxylysine may also beused. The recognition sequences for enzymatic attachment of thecarbohydrate moiety to the asparagine side chain peptide sequences areasparagine-X-serine and asparagine-X-threonine, where X is any aminoacid except proline. Thus, the presence of either of these peptidesequences in a polypeptide creates a potential glycosylation site.

The glycosylation pattern may be altered, for example, by deleting oneor more glycosylation site(s) found in the polypeptide, and/or addingone or more glycosylation sites that are not present in the polypeptide.Addition of glycosylation sites to the Fc region of a human IL-23specific antibody is conveniently accomplished by altering the aminoacid sequence such that it contains one or more of the above-describedtripeptide sequences (for N-linked glycosylation sites). An exemplaryglycosylation variant has an amino acid substitution of residue Asn 297of the heavy chain. The alteration may also be made by the addition of,or substitution by, one or more serine or threonine residues to thesequence of the original polypeptide (for O-linked glycosylation sites).Additionally, a change of Asn 297 to Ala can remove one of theglycosylation sites.

In certain embodiments, the human IL-23 specific antibody of the presentinvention is expressed in cells that express beta(1,4)-N-acetylglucosaminyltransferase III (GnT III), such that GnT IIIadds GlcNAc to the human IL-23 antibody. Methods for producingantibodies in such a fashion are provided in WO/9954342, WO/03011878,patent publication 20030003097A1, and Umana et al., NatureBiotechnology, 17:176-180, February 1999; all of which are hereinspecifically incorporated by reference in their entireties.

The anti-IL-23 antibody can also be optionally generated by immunizationof a transgenic animal (e.g., mouse, rat, hamster, non-human primate,and the like) capable of producing a repertoire of human antibodies, asdescribed herein and/or as known in the art. Cells that produce a humananti-IL-23 antibody can be isolated from such animals and immortalizedusing suitable methods, such as the methods described herein.

Transgenic mice that can produce a repertoire of human antibodies thatbind to human antigens can be produced by known methods (e.g., but notlimited to, U.S. Pat. Nos.: 5,770,428, 5,569,825, 5,545,806, 5,625,126,5,625,825, 5,633,425, 5,661,016 and 5,789,650 issued to Lonberg et al.;Jakobovits et al. WO 98/50433, Jakobovits et al. WO 98/24893, Lonberg etal. WO 98/24884, Lonberg et al. WO 97/13852, Lonberg et al. WO 94/25585,Kucherlapate et al. WO 96/34096, Kucherlapate et al. EP 0463 151 B1,Kucherlapate et al. EP 0710 719 A1, Surani et al. U.S. Pat. No.5,545,807, Bruggemann et al. WO 90/04036, Bruggemann et al. EP 0438 474B1, Lonberg et al. EP 0814 259 A2, Lonberg et al. GB 2 272 440 A,Lonberg et al. Nature 368:856-859 (1994), Taylor et al., Int. Immunol.6(4)579-591 (1994), Green et al, Nature Genetics 7:13-21 (1994), Mendezet al., Nature Genetics 15:146-156 (1997), Taylor et al., Nucleic AcidsResearch 20(23):6287-6295 (1992), Tuaillon et al., Proc Natl Acad SciUSA 90(8)3720-3724 (1993), Lonberg et al., Int Rev Immunol 13(1):65-93(1995) and Fishwald et al., Nat Biotechnol 14(7):845-851 (1996), whichare each entirely incorporated herein by reference). Generally, thesemice comprise at least one transgene comprising DNA from at least onehuman immunoglobulin locus that is functionally rearranged, or which canundergo functional rearrangement. The endogenous immunoglobulin loci insuch mice can be disrupted or deleted to eliminate the capacity of theanimal to produce antibodies encoded by endogenous genes.

Screening antibodies for specific binding to similar proteins orfragments can be conveniently achieved using peptide display libraries.This method involves the screening of large collections of peptides forindividual members having the desired function or structure. Antibodyscreening of peptide display libraries is well known in the art. Thedisplayed peptide sequences can be from 3 to 5000 or more amino acids inlength, frequently from 5-100 amino acids long, and often from about 8to 25 amino acids long. In addition to direct chemical synthetic methodsfor generating peptide libraries, several recombinant DNA methods havebeen described. One type involves the display of a peptide sequence onthe surface of a bacteriophage or cell. Each bacteriophage or cellcontains the nucleotide sequence encoding the particular displayedpeptide sequence. Such methods are described in PCT Patent PublicationNos. 91/17271, 91/18980, 91/19818, and 93/08278.

Other systems for generating libraries of peptides have aspects of bothin vitro chemical synthesis and recombinant methods. See, PCT PatentPublication Nos. 92/05258, 92/14843, and 96/19256. See also, U.S. Pat.Nos. 5,658,754; and 5,643,768. Peptide display libraries, vector, andscreening kits are commercially available from such suppliers asInvitrogen (Carlsbad, Calif.), and Cambridge antibody Technologies(Cambridgeshire, UK). See, e.g., U.S. Pat. Nos. 4,704,692, 4,939,666,4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730,5,763,733, 5,767,260, 5,856,456, assigned to Enzon; U.S. Pat. Nos.5,223,409, 5,403,484, 5,571,698, 5,837,500, assigned to Dyax, U.S. Pat.Nos. 5,427,908, 5,580,717, assigned to Affymax; U.S. Pat. No. 5,885,793,assigned to Cambridge antibody Technologies; U.S. Pat. No. 5,750,373,assigned to Genentech, U.S. Pat. Nos. 5,618,920, 5,595,898, 5,576,195,5,698,435, 5,693,493, 5,698,417, assigned to Xoma, Colligan, supra;Ausubel, supra; or Sambrook, supra, each of the above patents andpublications entirely incorporated herein by reference.

Antibodies used in the method of the present invention can also beprepared using at least one anti-IL23 antibody encoding nucleic acid toprovide transgenic animals or mammals, such as goats, cows, horses,sheep, rabbits, and the like, that produce such antibodies in theirmilk. Such animals can be provided using known methods. See, e.g., butnot limited to, U.S. Pat. Nos. 5,827,690; 5,849,992; 4,873,316;5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like, each of whichis entirely incorporated herein by reference.

Antibodies used in the method of the present invention can additionallybe prepared using at least one anti-IL23 antibody encoding nucleic acidto provide transgenic plants and cultured plant cells (e.g., but notlimited to, tobacco and maize) that produce such antibodies, specifiedportions or variants in the plant parts or in cells cultured therefrom.As a non-limiting example, transgenic tobacco leaves expressingrecombinant proteins have been successfully used to provide largeamounts of recombinant proteins, e.g., using an inducible promoter. See,e.g., Cramer et al., Curr. Top. Microbol. Immunol. 240:95-118 (1999) andreferences cited therein. Also, transgenic maize have been used toexpress mammalian proteins at commercial production levels, withbiological activities equivalent to those produced in other recombinantsystems or purified from natural sources. See, e.g., Hood et al., Adv.Exp. Med. Biol. 464:127-147 (1999) and references cited therein.Antibodies have also been produced in large amounts from transgenicplant seeds including antibody fragments, such as single chainantibodies (scFv's), including tobacco seeds and potato tubers. See,e.g., Conrad et al., Plant Mol. Biol. 38:101-109 (1998) and referencescited therein. Thus, antibodies of the present invention can also beproduced using transgenic plants, according to known methods. See also,e.g., Fischer et al., Biotechnol. Appl. Biochem. 30:99-108 (October,1999), Ma et al., Trends Biotechnol. 13:522-7 (1995); Ma et al., PlantPhysiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans.22:940-944 (1994); and references cited therein. Each of the abovereferences is entirely incorporated herein by reference.

The antibodies used in the method of the invention can bind human IL-23with a wide range of affinities (K_(D)). In a preferred embodiment, ahuman mAb can optionally bind human IL-23 with high affinity. Forexample, a human mAb can bind human IL-23 with a K_(D) equal to or lessthan about 10⁻⁷M, such as but not limited to, 0.1-9.9 (or any range orvalue therein)×10⁻⁷, 10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³ or any rangeor value therein.

The affinity or avidity of an antibody for an antigen can be determinedexperimentally using any suitable method. (See, for example, Berzofsky,et al., “Antibody-Antigen Interactions,” In Fundamental Immunology,Paul, W. E., Ed., Raven Press: New York, N.Y. (1984); Kuby, JanisImmunology, W. H. Freeman and Company: New York, N.Y. (1992); andmethods described herein). The measured affinity of a particularantibody-antigen interaction can vary if measured under differentconditions (e.g., salt concentration, pH). Thus, measurements ofaffinity and other antigen-binding parameters (e.g., K_(D), K_(a),K_(d)) are preferably made with standardized solutions of antibody andantigen, and a standardized buffer, such as the buffer described herein.

Nucleic Acid Molecules

Using the information provided herein, for example, the nucleotidesequences encoding at least 70-100% of the contiguous amino acids of atleast one of the light or heavy chain variable or CDR regions describedherein, among other sequences disclosed herein, specified fragments,variants or consensus sequences thereof, or a deposited vectorcomprising at least one of these sequences, a nucleic acid molecule ofthe present invention encoding at least one anti-IL-23 antibody can beobtained using methods described herein or as known in the art.

Nucleic acid molecules of the present invention can be in the form ofRNA, such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA,including, but not limited to, cDNA and genomic DNA obtained by cloningor produced synthetically, or any combinations thereof. The DNA can betriple-stranded, double-stranded or single-stranded, or any combinationthereof. Any portion of at least one strand of the DNA or RNA can be thecoding strand, also known as the sense strand, or it can be thenon-coding strand, also referred to as the anti-sense strand.

Isolated nucleic acid molecules used in the method of the presentinvention can include nucleic acid molecules comprising an open readingframe (ORF), optionally, with one or more introns, e.g., but not limitedto, at least one specified portion of at least one CDR, such as CDR1,CDR2 and/or CDR3 of at least one heavy chain or light chain; nucleicacid molecules comprising the coding sequence for an anti-IL-23 antibodyor variable region; and nucleic acid molecules which comprise anucleotide sequence substantially different from those described abovebut which, due to the degeneracy of the genetic code, still encode atleast one anti-IL-23 antibody as described herein and/or as known in theart. Of course, the genetic code is well known in the art. Thus, itwould be routine for one skilled in the art to generate such degeneratenucleic acid variants that code for specific anti-IL-23 antibodies usedin the method of the present invention. See, e.g., Ausubel, et al.,supra, and such nucleic acid variants are included in the presentinvention. Non-limiting examples of isolated nucleic acid moleculesinclude nucleic acids encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LCCDR2, and LC CDR3, respectively.

As indicated herein, nucleic acid molecules which comprise a nucleicacid encoding an anti-IL-23 antibody can include, but are not limitedto, those encoding the amino acid sequence of an antibody fragment, byitself; the coding sequence for the entire antibody or a portionthereof; the coding sequence for an antibody, fragment or portion, aswell as additional sequences, such as the coding sequence of at leastone signal leader or fusion peptide, with or without the aforementionedadditional coding sequences, such as at least one intron, together withadditional, non-coding sequences, including but not limited to,non-coding 5′ and 3′ sequences, such as the transcribed, non-translatedsequences that play a role in transcription, mRNA processing, includingsplicing and polyadenylation signals (for example, ribosome binding andstability of mRNA); an additional coding sequence that codes foradditional amino acids, such as those that provide additionalfunctionalities. Thus, the sequence encoding an antibody can be fused toa marker sequence, such as a sequence encoding a peptide thatfacilitates purification of the fused antibody comprising an antibodyfragment or portion.

Polynucleotides Selectively Hybridizing to a Polynucleotide as DescribedHerein

The method of the present invention uses isolated nucleic acids thathybridize under selective hybridization conditions to a polynucleotidedisclosed herein. Thus, the polynucleotides of this embodiment can beused for isolating, detecting, and/or quantifying nucleic acidscomprising such polynucleotides. For example, polynucleotides of thepresent invention can be used to identify, isolate, or amplify partialor full-length clones in a deposited library. In some embodiments, thepolynucleotides are genomic or cDNA sequences isolated, or otherwisecomplementary to, a cDNA from a human or mammalian nucleic acid library.

Preferably, the cDNA library comprises at least 80% full-lengthsequences, preferably, at least 85% or 90% full-length sequences, and,more preferably, at least 95% full-length sequences. The cDNA librariescan be normalized to increase the representation of rare sequences. Lowor moderate stringency hybridization conditions are typically, but notexclusively, employed with sequences having a reduced sequence identityrelative to complementary sequences. Moderate and high stringencyconditions can optionally be employed for sequences of greater identity.Low stringency conditions allow selective hybridization of sequenceshaving about 70% sequence identity and can be employed to identifyorthologous or paralogous sequences.

Optionally, polynucleotides will encode at least a portion of anantibody. The polynucleotides embrace nucleic acid sequences that can beemployed for selective hybridization to a polynucleotide encoding anantibody of the present invention. See, e.g., Ausubel, supra; Colligan,supra, each entirely incorporated herein by reference.

Construction of Nucleic Acids

The isolated nucleic acids can be made using (a) recombinant methods,(b) synthetic techniques, (c) purification techniques, and/or (d)combinations thereof, as well-known in the art.

The nucleic acids can conveniently comprise sequences in addition to apolynucleotide of the present invention. For example, a multi-cloningsite comprising one or more endonuclease restriction sites can beinserted into the nucleic acid to aid in isolation of thepolynucleotide. Also, translatable sequences can be inserted to aid inthe isolation of the translated polynucleotide of the present invention.For example, a hexa-histidine marker sequence provides a convenientmeans to purify the proteins of the present invention. The nucleic acidof the present invention, excluding the coding sequence, is optionally avector, adapter, or linker for cloning and/or expression of apolynucleotide of the present invention.

Additional sequences can be added to such cloning and/or expressionsequences to optimize their function in cloning and/or expression, toaid in isolation of the polynucleotide, or to improve the introductionof the polynucleotide into a cell. Use of cloning vectors, expressionvectors, adapters, and linkers is well known in the art. (See, e.g.,Ausubel, supra; or Sambrook, supra).

Recombinant Methods for Constructing Nucleic Acids

The isolated nucleic acid compositions, such as RNA, cDNA, genomic DNA,or any combination thereof, can be obtained from biological sourcesusing any number of cloning methodologies known to those of skill in theart. In some embodiments, oligonucleotide probes that selectivelyhybridize, under stringent conditions, to the polynucleotides of thepresent invention are used to identify the desired sequence in a cDNA orgenomic DNA library. The isolation of RNA, and construction of cDNA andgenomic libraries, are well known to those of ordinary skill in the art.(See, e.g., Ausubel, supra; or Sambrook, supra)

Nucleic Acid Screening and Isolation Methods

A cDNA or genomic library can be screened using a probe based upon thesequence of a polynucleotide used in the method of the presentinvention, such as those disclosed herein. Probes can be used tohybridize with genomic DNA or cDNA sequences to isolate homologous genesin the same or different organisms. Those of skill in the art willappreciate that various degrees of stringency of hybridization can beemployed in the assay; and either the hybridization or the wash mediumcan be stringent. As the conditions for hybridization become morestringent, there must be a greater degree of complementarity between theprobe and the target for duplex formation to occur. The degree ofstringency can be controlled by one or more of temperature, ionicstrength, pH and the presence of a partially denaturing solvent, such asformamide. For example, the stringency of hybridization is convenientlyvaried by changing the polarity of the reactant solution through, forexample, manipulation of the concentration of formamide within the rangeof 0% to 50%. The degree of complementarity (sequence identity) requiredfor detectable binding will vary in accordance with the stringency ofthe hybridization medium and/or wash medium. The degree ofcomplementarity will optimally be 100%, or 70-100%, or any range orvalue therein. However, it should be understood that minor sequencevariations in the probes and primers can be compensated for by reducingthe stringency of the hybridization and/or wash medium.

Methods of amplification of RNA or DNA are well known in the art and canbe used according to the present invention without undueexperimentation, based on the teaching and guidance presented herein.

Known methods of DNA or RNA amplification include, but are not limitedto, polymerase chain reaction (PCR) and related amplification processes(see, e.g., U.S. Pat. Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188,to Mullis, et al.; 4,795,699 and 4,921,794 to Tabor, et al; 5,142,033 toInnis; 5,122,464 to Wilson, et al.; 5,091,310 to Innis; 5,066,584 toGyllensten, et al; 4,889,818 to Gelfand, et al; 4,994,370 to Silver, etal; 4,766,067 to Biswas; 4,656,134 to Ringold) and RNA mediatedamplification that uses anti-sense RNA to the target sequence as atemplate for double-stranded DNA synthesis (U.S. Pat. No. 5,130,238 toMalek, et al, with the tradename NASBA), the entire contents of whichreferences are incorporated herein by reference. (See, e.g., Ausubel,supra; or Sambrook, supra.)

For instance, polymerase chain reaction (PCR) technology can be used toamplify the sequences of polynucleotides used in the method of thepresent invention and related genes directly from genomic DNA or cDNAlibraries. PCR and other in vitro amplification methods can also beuseful, for example, to clone nucleic acid sequences that code forproteins to be expressed, to make nucleic acids to use as probes fordetecting the presence of the desired mRNA in samples, for nucleic acidsequencing, or for other purposes. Examples of techniques sufficient todirect persons of skill through in vitro amplification methods are foundin Berger, supra, Sambrook, supra, and Ausubel, supra, as well asMullis, et al., U.S. Pat. No. 4,683,202 (1987); and Innis, et al., PCRProtocols A Guide to Methods and Applications, Eds., Academic PressInc., San Diego, Calif. (1990). Commercially available kits for genomicPCR amplification are known in the art. See, e.g., Advantage-GC GenomicPCR Kit (Clontech). Additionally, e.g., the T4 gene 32 protein(Boehringer Mannheim) can be used to improve yield of long PCR products.

Synthetic Methods for Constructing Nucleic Acids

The isolated nucleic acids used in the method of the present inventioncan also be prepared by direct chemical synthesis by known methods (see,e.g., Ausubel, et al., supra). Chemical synthesis generally produces asingle-stranded oligonucleotide, which can be converted intodouble-stranded DNA by hybridization with a complementary sequence, orby polymerization with a DNA polymerase using the single strand as atemplate. One of skill in the art will recognize that while chemicalsynthesis of DNA can be limited to sequences of about 100 or more bases,longer sequences can be obtained by the ligation of shorter sequences.

Recombinant Expression Cassettes

The present invention uses recombinant expression cassettes comprising anucleic acid. A nucleic acid sequence, for example, a cDNA or a genomicsequence encoding an antibody used in the method of the presentinvention, can be used to construct a recombinant expression cassettethat can be introduced into at least one desired host cell. Arecombinant expression cassette will typically comprise a polynucleotideoperably linked to transcriptional initiation regulatory sequences thatwill direct the transcription of the polynucleotide in the intended hostcell. Both heterologous and non-heterologous (i.e., endogenous)promoters can be employed to direct expression of the nucleic acids.

In some embodiments, isolated nucleic acids that serve as promoter,enhancer, or other elements can be introduced in the appropriateposition (upstream, downstream or in the intron) of a non-heterologousform of a polynucleotide of the present invention so as to up or downregulate expression of a polynucleotide. For example, endogenouspromoters can be altered in vivo or in vitro by mutation, deletionand/or substitution.

Vectors and Host Cells

The present invention also relates to vectors that include isolatednucleic acid molecules, host cells that are genetically engineered withthe recombinant vectors, and the production of at least one anti-IL-23antibody by recombinant techniques, as is well known in the art. See,e.g., Sambrook, et al., supra; Ausubel, et al., supra, each entirelyincorporated herein by reference.

The polynucleotides can optionally be joined to a vector containing aselectable marker for propagation in a host. Generally, a plasmid vectoris introduced in a precipitate, such as a calcium phosphate precipitate,or in a complex with a charged lipid. If the vector is a virus, it canbe packaged in vitro using an appropriate packaging cell line and thentransduced into host cells.

The DNA insert should be operatively linked to an appropriate promoter.The expression constructs will further contain sites for transcriptioninitiation, termination and, in the transcribed region, a ribosomebinding site for translation. The coding portion of the maturetranscripts expressed by the constructs will preferably include atranslation initiating at the beginning and a termination codon (e.g.,UAA, UGA or UAG) appropriately positioned at the end of the mRNA to betranslated, with UAA and UAG preferred for mammalian or eukaryotic cellexpression.

Expression vectors will preferably but optionally include at least oneselectable marker. Such markers include, e.g., but are not limited to,methotrexate (MTX), dihydrofolate reductase (DHFR, U.S. Pat. Nos.4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017,ampicillin, neomycin (G418), mycophenolic acid, or glutamine synthetase(GS, U.S. Pat. Nos. 5,122,464; 5,770,359; 5,827,739) resistance foreukaryotic cell culture, and tetracycline or ampicillin resistance genesfor culturing in E. coli and other bacteria or prokaryotics (the abovepatents are entirely incorporated hereby by reference). Appropriateculture mediums and conditions for the above-described host cells areknown in the art. Suitable vectors will be readily apparent to theskilled artisan. Introduction of a vector construct into a host cell canbe effected by calcium phosphate transfection, DEAE-dextran mediatedtransfection, cationic lipid-mediated transfection, electroporation,transduction, infection or other known methods. Such methods aredescribed in the art, such as Sambrook, supra, Chapters 1-4 and 16-18;Ausubel, supra, Chapters 1, 9, 13, 15, 16.

At least one antibody used in the method of the present invention can beexpressed in a modified form, such as a fusion protein, and can includenot only secretion signals, but also additional heterologous functionalregions. For instance, a region of additional amino acids, particularlycharged amino acids, can be added to the N-terminus of an antibody toimprove stability and persistence in the host cell, during purification,or during subsequent handling and storage. Also, peptide moieties can beadded to an antibody of the present invention to facilitatepurification. Such regions can be removed prior to final preparation ofan antibody or at least one fragment thereof. Such methods are describedin many standard laboratory manuals, such as Sambrook, supra, Chapters17.29-17.42 and 18.1-18.74; Ausubel, supra, Chapters 16, 17 and 18.

Those of ordinary skill in the art are knowledgeable in the numerousexpression systems available for expression of a nucleic acid encoding aprotein used in the method of the present invention. Alternatively,nucleic acids can be expressed in a host cell by turning on (bymanipulation) in a host cell that contains endogenous DNA encoding anantibody. Such methods are well known in the art, e.g., as described inU.S. Pat. Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761, entirelyincorporated herein by reference.

Illustrative of cell cultures useful for the production of theantibodies, specified portions or variants thereof, are mammalian cells.Mammalian cell systems often will be in the form of monolayers of cellsalthough mammalian cell suspensions or bioreactors can also be used. Anumber of suitable host cell lines capable of expressing intactglycosylated proteins have been developed in the art, and include theCOS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL-1651), HEK293, BHK21(e.g., ATCC CRL-10), CHO (e.g., ATCC CRL 1610) and BSC-1 (e.g., ATCCCRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653,SP2/0-Ag14, 293 cells, HeLa cells and the like, which are readilyavailable from, for example, American Type Culture Collection, Manassas,Va. (www.atcc.org). Preferred host cells include cells of lymphoidorigin, such as myeloma and lymphoma cells. Particularly preferred hostcells are P3X63Ag8.653 cells (ATCC Accession Number CRL-1580) andSP2/0-Ag14 cells (ATCC Accession Number CRL-1851). In a particularlypreferred embodiment, the recombinant cell is a P3X63Ab8.653 or aSP2/0-Ag14 cell.

Expression vectors for these cells can include one or more of thefollowing expression control sequences, such as, but not limited to, anorigin of replication; a promoter (e.g., late or early SV40 promoters,the CMV promoter (U.S. Pat. Nos. 5,168,062; 5,385,839), an HSV tkpromoter, a pgk (phosphoglycerate kinase) promoter, an EF-1 alphapromoter (U.S. Pat. No. 5,266,491), at least one human immunoglobulinpromoter; an enhancer, and/or processing information sites, such asribosome binding sites, RNA splice sites, polyadenylation sites (e.g.,an SV40 large T Ag poly A addition site), and transcriptional terminatorsequences. See, e.g., Ausubel et al., supra; Sambrook, et al., supra.Other cells useful for production of nucleic acids or proteins of thepresent invention are known and/or available, for instance, from theAmerican Type Culture Collection Catalogue of Cell Lines and Hybridomas(www.atcc.org) or other known or commercial sources.

When eukaryotic host cells are employed, polyadenlyation ortranscription terminator sequences are typically incorporated into thevector. An example of a terminator sequence is the polyadenlyationsequence from the bovine growth hormone gene. Sequences for accuratesplicing of the transcript can also be included. An example of asplicing sequence is the VP1 intron from SV40 (Sprague, et al., J.Virol. 45:773-781 (1983)). Additionally, gene sequences to controlreplication in the host cell can be incorporated into the vector, asknown in the art.

Purification of an Antibody

An anti-IL-23 antibody can be recovered and purified from recombinantcell cultures by well-known methods including, but not limited to,protein A purification, ammonium sulfate or ethanol precipitation, acidextraction, anion or cation exchange chromatography, phosphocellulosechromatography, hydrophobic interaction chromatography, affinitychromatography, hydroxylapatite chromatography and lectinchromatography. High performance liquid chromatography (“HPLC”) can alsobe employed for purification. See, e.g., Colligan, Current Protocols inImmunology, or Current Protocols in Protein Science, John Wiley & Sons,NY, N.Y., (1997-2001), e.g., Chapters 1, 4, 6, 8, 9, 10, each entirelyincorporated herein by reference.

Antibodies used in the method of the present invention include naturallypurified products, products of chemical synthetic procedures, andproducts produced by recombinant techniques from a eukaryotic host,including, for example, yeast, higher plant, insect and mammalian cells.Depending upon the host employed in a recombinant production procedure,the antibody can be glycosylated or can be non-glycosylated, withglycosylated preferred. Such methods are described in many standardlaboratory manuals, such as Sambrook, supra, Sections 17.37-17.42;Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20, Colligan, ProteinScience, supra, Chapters 12-14, all entirely incorporated herein byreference.

Anti-IL-23 Antibodies.

An anti-IL-23 antibody according to the present invention includes anyprotein or peptide containing molecule that comprises at least a portionof an immunoglobulin molecule, such as but not limited to, at least oneligand binding portion (LBP), such as but not limited to, acomplementarity determining region (CDR) of a heavy or light chain or aligand binding portion thereof, a heavy chain or light chain variableregion, a framework region (e.g., FR1, FR2, FR3, FR4 or fragmentthereof, further optionally comprising at least one substitution,insertion or deletion), a heavy chain or light chain constant region,(e.g., comprising at least one C_(H)1, hinge1, hinge2, hinge3, hinge4,C_(H)2, or C_(H)3 or fragment thereof, further optionally comprising atleast one substitution, insertion or deletion), or any portion thereof,that can be incorporated into an antibody. An antibody can include or bederived from any mammal, such as but not limited to, a human, a mouse, arabbit, a rat, a rodent, a primate, or any combination thereof, and thelike.

The isolated antibodies used in the method of the present inventioncomprise the antibody amino acid sequences disclosed herein encoded byany suitable polynucleotide, or any isolated or prepared antibody.Preferably, the human antibody or antigen-binding fragment binds humanIL-23 and, thereby, partially or substantially neutralizes at least onebiological activity of the protein. An antibody, or specified portion orvariant thereof, that partially or preferably substantially neutralizesat least one biological activity of at least one IL-23 protein orfragment can bind the protein or fragment and thereby inhibit activitiesmediated through the binding of IL-23 to the IL-23 receptor or throughother IL-23-dependent or mediated mechanisms. As used herein, the term“neutralizing antibody” refers to an antibody that can inhibit anIL-23-dependent activity by about 20-120%, preferably by at least about10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95,96, 97, 98, 99, 100% or more depending on the assay. The capacity of ananti-IL-23 antibody to inhibit an IL-23-dependent activity is preferablyassessed by at least one suitable IL-23 protein or receptor assay, asdescribed herein and/or as known in the art. A human antibody can be ofany class (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise akappa or lambda light chain. In one embodiment, the human antibodycomprises an IgG heavy chain or defined fragment, for example, at leastone of isotypes, IgG1, IgG2, IgG3 or IgG4 (e.g., γ1, γ2, γ3, γ4).Antibodies of this type can be prepared by employing a transgenic mouseor other trangenic non-human mammal comprising at least one human lightchain (e.g., IgG, IgA, and IgM) transgenes as described herein and/or asknown in the art. In another embodiment, the anti-IL-23 human antibodycomprises an IgG1 heavy chain and an IgG1 light chain.

An antibody binds at least one specified epitope specific to at leastone IL-23 protein, subunit, fragment, portion or any combinationthereof. The at least one epitope can comprise at least one antibodybinding region that comprises at least one portion of the protein, whichepitope is preferably comprised of at least one extracellular, soluble,hydrophillic, external or cytoplasmic portion of the protein.

Generally, the human antibody or antigen-binding fragment will comprisean antigen-binding region that comprises at least one humancomplementarity determining region (CDR1, CDR2 and CDR3) or variant ofat least one heavy chain variable region and at least one humancomplementarity determining region (CDR1, CDR2 and CDR3) or variant ofat least one light chain variable region. The CDR sequences may bederived from human germline sequences or closely match the germlinesequences. For example, the CDRs from a synthetic library derived fromthe original non-human CDRs can be used. These CDRs may be formed byincorporation of conservative substitutions from the original non-humansequence. In another particular embodiment, the antibody orantigen-binding portion or variant can have an antigen-binding regionthat comprises at least a portion of at least one light chain CDR (i.e.,CDR1, CDR2 and/or CDR3) having the amino acid sequence of thecorresponding CDRs 1, 2 and/or 3.

Such antibodies can be prepared by chemically joining together thevarious portions (e.g., CDRs, framework) of the antibody usingconventional techniques, by preparing and expressing a (i.e., one ormore) nucleic acid molecule that encodes the antibody using conventionaltechniques of recombinant DNA technology or by using any other suitablemethod.

The anti-IL-23 specific antibody can comprise at least one of a heavy orlight chain variable region having a defined amino acid sequence. Forexample, in a preferred embodiment, the anti-IL-23 antibody comprises atleast one of at least one heavy chain variable region, optionally havingthe amino acid sequence of SEQ ID NO:106 and/or at least one light chainvariable region, optionally having the amino acid sequence of SEQ IDNO:116. Antibodies that bind to human IL-23 and that comprise a definedheavy or light chain variable region can be prepared using suitablemethods, such as phage display (Katsube, Y., et al., Int J Mol. Med,1(5):863-868 (1998)) or methods that employ transgenic animals, as knownin the art and/or as described herein. For example, a transgenic mouse,comprising a functionally rearranged human immunoglobulin heavy chaintransgene and a transgene comprising DNA from a human immunoglobulinlight chain locus that can undergo functional rearrangement, can beimmunized with human IL-23 or a fragment thereof to elicit theproduction of antibodies. If desired, the antibody producing cells canbe isolated and hybridomas or other immortalized antibody-producingcells can be prepared as described herein and/or as known in the art.Alternatively, the antibody, specified portion or variant can beexpressed using the encoding nucleic acid or portion thereof in asuitable host cell.

The invention also relates to antibodies, antigen-binding fragments,immunoglobulin chains and CDRs comprising amino acids in a sequence thatis substantially the same as an amino acid sequence described herein.Preferably, such antibodies or antigen-binding fragments and antibodiescomprising such chains or CDRs can bind human IL-23 with high affinity(e.g., K_(D) less than or equal to about 10⁻⁹ M). Amino acid sequencesthat are substantially the same as the sequences described hereininclude sequences comprising conservative amino acid substitutions, aswell as amino acid deletions and/or insertions. A conservative aminoacid substitution refers to the replacement of a first amino acid by asecond amino acid that has chemical and/or physical properties (e.g.,charge, structure, polarity, hydrophobicity/hydrophilicity) that aresimilar to those of the first amino acid. Conservative substitutionsinclude, without limitation, replacement of one amino acid by anotherwithin the following groups: lysine (K), arginine (R) and histidine (H);aspartate (D) and glutamate (E); asparagine (N), glutamine (Q), serine(S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine(V), leucine (L), isoleucine (I), proline (P), phenylalanine (F),tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W andY; C, S and T.

Amino Acid Codes

The amino acids that make up anti-IL-23 antibodies of the presentinvention are often abbreviated. The amino acid designations can beindicated by designating the amino acid by its single letter code, itsthree letter code, name, or three nucleotide codon(s) as is wellunderstood in the art (see Alberts, B., et al., Molecular Biology of TheCell, Third Ed., Garland Publishing, Inc., New York, 1994):

SINGLE THREE THREE LETTER LETTER NUCLEOTIDE CODE CODE NAME CODON(S) AAla Alanine GCA, GCC, GCG, GCU C Cys Cysteine UGC, UGU D Asp Asparticacid GAC, GAU E Glu Glutamic acid GAA, GAG F Phe Phenylanine UUC, UUU GGly Glycine GGA, GGC, GGG, GGU H His Histidine CAC, CAU I Ile IsoleucineAUA, AUC, AUU K Lys Lysine AAA, AAG L Leu Leucine UUA, UUG, CUA, CUC,CUG, CUU M Met Methionine AUG N Asn Asparagine AAC, AAU P Pro ProlineCCA, CCC, CCG, CCU Q Gln Glutamine CAA, CAG R Arg Arginine AGA, AGG,CGA, CGC, CGG, CGU S Ser Serine AGC, AGU, UCA, UCC, UCG, UCU T ThrThreonine ACA, ACC, ACG, ACU V Val Valine GUA, GUC, GUG, GUU W TrpTryptophan UGG Y Tyr Tyrosine UAC, UAUAn anti-IL-23 antibody used in the method of the present invention caninclude one or more amino acid substitutions, deletions or additions,either from natural mutations or human manipulation, as specifiedherein.

The number of amino acid substitutions a skilled artisan would makedepends on many factors, including those described above. Generallyspeaking, the number of amino acid substitutions, insertions ordeletions for any given anti-IL-23 antibody, fragment or variant willnot be more than 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9,8, 7, 6, 5, 4, 3, 2, 1, such as 1-30 or any range or value therein, asspecified herein.

Amino acids in an anti-IL-23 specific antibody that are essential forfunction can be identified by methods known in the art, such assite-directed mutagenesis or alanine-scanning mutagenesis (e.g.,Ausubel, supra, Chapters 8, 15; Cunningham and Wells, Science244:1081-1085 (1989)). The latter procedure introduces single alaninemutations at every residue in the molecule. The resulting mutantmolecules are then tested for biological activity, such as, but notlimited to, at least one IL-23 neutralizing activity. Sites that arecritical for antibody binding can also be identified by structuralanalysis, such as crystallization, nuclear magnetic resonance orphotoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992)and de Vos, et al., Science 255:306-312 (1992)).

Anti-IL-23 antibodies can include, but are not limited to, at least oneportion, sequence or combination selected from 5 to all of thecontiguous amino acids of at least one of SEQ ID NOS: 5, 20, 44, 50, 56,and 73.

IL-23 antibodies or specified portions or variants can include, but arenot limited to, at least one portion, sequence or combination selectedfrom at least 3-5 contiguous amino acids of the SEQ ID NOs above; 5-17contiguous amino acids of the SEQ ID NOs above, 5-10 contiguous aminoacids of the SEQ ID NOs above, 5-11 contiguous amino acids of the SEQ IDNOs above, 5-7 contiguous amino acids of the SEQ ID NOs above; 5-9contiguous amino acids of the SEQ ID NOs above.

An anti-IL-23 antibody can further optionally comprise a polypeptide ofat least one of 70-100% of 5, 17, 10, 11, 7, 9, 119, or 108 contiguousamino acids of the SEQ ID NOs above. In one embodiment, the amino acidsequence of an immunoglobulin chain, or portion thereof (e.g., variableregion, CDR) has about 70-100% identity (e.g., 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100 or any range or value therein) to the aminoacid sequence of the corresponding chain of at least one of the SEQ IDNOs above. For example, the amino acid sequence of a light chainvariable region can be compared with the sequence of the SEQ ID NOsabove, or the amino acid sequence of a heavy chain CDR3 can be comparedwith the SEQ ID NOs above. Preferably, 70-100% amino acid identity(i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or valuetherein) is determined using a suitable computer algorithm, as known inthe art.

“Identity,” as known in the art, is a relationship between two or morepolypeptide sequences or two or more polynucleotide sequences, asdetermined by comparing the sequences. In the art, “identity” also meansthe degree of sequence relatedness between polypeptide or polynucleotidesequences, as determined by the match between strings of such sequences.“Identity” and “similarity” can be readily calculated by known methods,including, but not limited to, those described in ComputationalMolecular Biology, Lesk, A. M., ed., Oxford University Press, New York,1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed.,Academic Press, New York, 1993; Computer Analysis of Sequence Data, PartI, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey,1994; Sequence Analysis in Molecular Biology, von Heinje, G., AcademicPress, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux,J., eds., M Stockton Press, New York, 1991; and Carillo, H., and Lipman,D., Siam J. Applied Math., 48:1073 (1988). In addition, values forpercentage identity can be obtained from amino acid and nucleotidesequence alignments generated using the default settings for the AlignXcomponent of Vector NTI Suite 8.0 (Informax, Frederick, Md.).

Preferred methods to determine identity are designed to give the largestmatch between the sequences tested. Methods to determine identity andsimilarity are codified in publicly available computer programs.Preferred computer program methods to determine identity and similaritybetween two sequences include, but are not limited to, the GCG programpackage (Devereux, J., et al., Nucleic Acids Research 12(1): 387(1984)), BLASTP, BLASTN, and FASTA (Atschul, S. F. et al., J. Molec.Biol. 215:403-410 (1990)). The BLAST X program is publicly availablefrom NCBI and other sources (BLAST Manual, Altschul, S., et al., NCBINLMNIH Bethesda, Md. 20894: Altschul, S., et al., J. Mol. Biol. 215:403-410(1990). The well-known Smith Waterman algorithm may also be used todetermine identity.

Preferred parameters for polypeptide sequence comparison include thefollowing:

(1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970)Comparison matrix: BLOSSUM62 from Hentikoff and Hentikoff, Proc. Natl.Acad. Sci, USA. 89:10915-10919 (1992)

Gap Penalty: 12

Gap Length Penalty: 4

A program useful with these parameters is publicly available as the“gap” program from Genetics Computer Group, Madison Wis. Theaforementioned parameters are the default parameters for peptidesequence comparisons (along with no penalty for end gaps).

Preferred parameters for polynucleotide comparison include thefollowing:

(1) Algorithm: Needleman and Wunsch, J. Mol Biol. 48:443-453 (1970)

Comparison matrix: matches=+10, mismatch=0

Gap Penalty: 50

Gap Length Penalty: 3

Available as: The “gap” program from Genetics Computer Group, MadisonWis. These are the default parameters for nucleic acid sequencecomparisons.

By way of example, a polynucleotide sequence may be identical to anothersequence, that is 100% identical, or it may include up to a certaininteger number of nucleotide alterations as compared to the referencesequence. Such alterations are selected from the group consisting of atleast one nucleotide deletion, substitution, including transition andtransversion, or insertion, and wherein the alterations may occur at the5′ or 3′ terminal positions of the reference nucleotide sequence oranywhere between those terminal positions, interspersed eitherindividually among the nucleotides in the reference sequence or in oneor more contiguous groups within the reference sequence. The number ofnucleotide alterations is determined by multiplying the total number ofnucleotides in the sequence by the numerical percent of the respectivepercent identity (divided by 100) and subtracting that product from thetotal number of nucleotides in the sequence, or:

n.sub.n.1torsim.x.sub.n−(x.sub.n.y),

wherein n.sub.n is the number of nucleotide alterations, x.sub.n is thetotal number of nucleotides in sequence, and y is, for instance, 0.70for 70%, 0.80 for 80%, 0.85 for 85%, 0.90 for 90%, 0.95 for 95%, etc.,and wherein any non-integer product of x.sub.n and y is rounded down tothe nearest integer prior to subtracting from x.sub.n.

Alterations of a polynucleotide sequence encoding the the SEQ ID NOsabove may create nonsense, missense or frameshift mutations in thiscoding sequence and thereby alter the polypeptide encoded by thepolynucleotide following such alterations. Similarly, a polypeptidesequence may be identical to the reference sequence of the SEQ ID NOsabove, that is be 100% identical, or it may include up to a certaininteger number of amino acid alterations as compared to the referencesequence such that the percentage identity is less than 100%. Suchalterations are selected from the group consisting of at least one aminoacid deletion, substitution, including conservative and non-conservativesubstitution, or insertion, and wherein the alterations may occur at theamino- or carboxy-terminal positions of the reference polypeptidesequence or anywhere between those terminal positions, interspersedeither individually among the amino acids in the reference sequence orin one or more contiguous groups within the reference sequence. Thenumber of amino acid alterations for a given % identity is determined bymultiplying the total number of amino acids in the SEQ ID NOs above bythe numerical percent of the respective percent identity (divided by100) and then subtracting that product from the total number of aminoacids in the SEQ ID NOs above, or:

n.sub.a.1torsim.x.sub.a−(x.sub.a.y),

wherein n.sub.a is the number of amino acid alterations, x.sub.a is thetotal number of amino acids in the SEQ ID NOs above, and y is, forinstance 0.70 for 70%, 0.80 for 80%, 0.85 for 85% etc., and wherein anynon-integer produce of x.sub.a and y is rounded down to the nearestinteger prior to subtracting it from x.sub.a.

Exemplary heavy chain and light chain variable regions sequences andportions thereof are provided in the SEQ ID NOs above. The antibodies ofthe present invention, or specified variants thereof, can comprise anynumber of contiguous amino acid residues from an antibody of the presentinvention, wherein that number is selected from the group of integersconsisting of from 10-100% of the number of contiguous residues in ananti-IL-23 antibody. Optionally, this subsequence of contiguous aminoacids is at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110,120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 ormore amino acids in length, or any range or value therein. Further, thenumber of such subsequences can be any integer selected from the groupconsisting of from 1 to 20, such as at least 2, 3, 4, or 5.

As those of skill will appreciate, the present invention includes atleast one biologically active antibody of the present invention.Biologically active antibodies have a specific activity at least 20%,30%, or 40%, and, preferably, at least 50%, 60%, or 70%, and, mostpreferably, at least 80%, 90%, or 95%-100% or more (including, withoutlimitation, up to 10 times the specific activity) of that of the native(non-synthetic), endogenous or related and known antibody. Methods ofassaying and quantifying measures of enzymatic activity and substratespecificity are well known to those of skill in the art.

In another aspect, the invention relates to human antibodies andantigen-binding fragments, as described herein, which are modified bythe covalent attachment of an organic moiety. Such modification canproduce an antibody or antigen-binding fragment with improvedpharmacokinetic properties (e.g., increased in vivo serum half-life).The organic moiety can be a linear or branched hydrophilic polymericgroup, fatty acid group, or fatty acid ester group. In particularembodiments, the hydrophilic polymeric group can have a molecular weightof about 800 to about 120,000 Daltons and can be a polyalkane glycol(e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)),carbohydrate polymer, amino acid polymer or polyvinyl pyrolidone, andthe fatty acid or fatty acid ester group can comprise from about eightto about forty carbon atoms.

The modified antibodies and antigen-binding fragments can comprise oneor more organic moieties that are covalently bonded, directly orindirectly, to the antibody. Each organic moiety that is bonded to anantibody or antigen-binding fragment of the invention can independentlybe a hydrophilic polymeric group, a fatty acid group or a fatty acidester group. As used herein, the term “fatty acid” encompassesmono-carboxylic acids and di-carboxylic acids. A “hydrophilic polymericgroup,” as the term is used herein, refers to an organic polymer that ismore soluble in water than in octane. For example, polylysine is moresoluble in water than in octane. Thus, an antibody modified by thecovalent attachment of polylysine is encompassed by the invention.Hydrophilic polymers suitable for modifying antibodies of the inventioncan be linear or branched and include, for example, polyalkane glycols(e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like),carbohydrates (e.g., dextran, cellulose, oligosaccharides,polysaccharides and the like), polymers of hydrophilic amino acids(e.g., polylysine, polyarginine, polyaspartate and the like), polyalkaneoxides (e.g., polyethylene oxide, polypropylene oxide and the like) andpolyvinyl pyrolidone. Preferably, the hydrophilic polymer that modifiesthe antibody of the invention has a molecular weight of about 800 toabout 150,000 Daltons as a separate molecular entity. For example,PEG₅₀₀₀ and PEG_(20,000,) wherein the subscript is the average molecularweight of the polymer in Daltons, can be used. The hydrophilic polymericgroup can be substituted with one to about six alkyl, fatty acid orfatty acid ester groups. Hydrophilic polymers that are substituted witha fatty acid or fatty acid ester group can be prepared by employingsuitable methods. For example, a polymer comprising an amine group canbe coupled to a carboxylate of the fatty acid or fatty acid ester, andan activated carboxylate (e.g., activated with N, N-carbonyldiimidazole) on a fatty acid or fatty acid ester can be coupled to ahydroxyl group on a polymer.

Fatty acids and fatty acid esters suitable for modifying antibodies ofthe invention can be saturated or can contain one or more units ofunsaturation. Fatty acids that are suitable for modifying antibodies ofthe invention include, for example, n-dodecanoate (C₁₂, laurate),n-tetradecanoate (C₁₄, myristate), n-octadecanoate (C₁₈, stearate),n-eicosanoate (C₂₀, arachidate), n-docosanoate (C₂₂, behenate),n-triacontanoate (C₃₀), n-tetracontanoate (C₄₀), cis-Δ9-octadecanoate(C₁₈, oleate), all cis-Δ5,8,11,14-eicosatetraenoate (C₂₀, arachidonate),octanedioic acid, tetradecanedioic acid, octadecanedioic acid,docosanedioic acid, and the like. Suitable fatty acid esters includemono-esters of dicarboxylic acids that comprise a linear or branchedlower alkyl group. The lower alkyl group can comprise from one to abouttwelve, preferably, one to about six, carbon atoms.

The modified human antibodies and antigen-binding fragments can beprepared using suitable methods, such as by reaction with one or moremodifying agents. A “modifying agent” as the term is used herein, refersto a suitable organic group (e.g., hydrophilic polymer, a fatty acid, afatty acid ester) that comprises an activating group. An “activatinggroup” is a chemical moiety or functional group that can, underappropriate conditions, react with a second chemical group therebyforming a covalent bond between the modifying agent and the secondchemical group. For example, amine-reactive activating groups includeelectrophilic groups, such as tosylate, mesylate, halo (chloro, bromo,fluoro, iodo), N-hydroxysuccinimidyl esters (NETS), and the like.Activating groups that can react with thiols include, for example,maleimide, iodoacetyl, acrylolyl, pyridyl disulfides,5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. An aldehydefunctional group can be coupled to amine- or hydrazide-containingmolecules, and an azide group can react with a trivalent phosphorousgroup to form phosphoramidate or phosphorimide linkages. Suitablemethods to introduce activating groups into molecules are known in theart (see for example, Hermanson, G. T., Bioconjugate Techniques,Academic Press: San Diego, Calif. (1996)). An activating group can bebonded directly to the organic group (e.g., hydrophilic polymer, fattyacid, fatty acid ester), or through a linker moiety, for example, adivalent C₁-C₁₂ group wherein one or more carbon atoms can be replacedby a heteroatom, such as oxygen, nitrogen or sulfur. Suitable linkermoieties include, for example, tetraethylene glycol, —(CH₂)₃—,—NH—(CH₂)₆—NH—, —(CH₂)₂—NH— and —CH₂—O—CH₂—CH₂—O—CH₂—CH₂—O—CH—NH—.Modifying agents that comprise a linker moiety can be produced, forexample, by reacting a mono-Boc-alkyldiamine (e.g.,mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid inthe presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) toform an amide bond between the free amine and the fatty acidcarboxylate. The Boc protecting group can be removed from the product bytreatment with trifluoroacetic acid (TFA) to expose a primary amine thatcan be coupled to another carboxylate, as described, or can be reactedwith maleic anhydride and the resulting product cyclized to produce anactivated maleimido derivative of the fatty acid. (See, for example,Thompson, et al., WO 92/16221, the entire teachings of which areincorporated herein by reference.)

The modified antibodies can be produced by reacting a human antibody orantigen-binding fragment with a modifying agent. For example, theorganic moieties can be bonded to the antibody in a non-site specificmanner by employing an amine-reactive modifying agent, for example, anNHS ester of PEG. Modified human antibodies or antigen-binding fragmentscan also be prepared by reducing disulfide bonds (e.g., intra-chaindisulfide bonds) of an antibody or antigen-binding fragment. The reducedantibody or antigen-binding fragment can then be reacted with athiol-reactive modifying agent to produce the modified antibody of theinvention. Modified human antibodies and antigen-binding fragmentscomprising an organic moiety that is bonded to specific sites of anantibody of the present invention can be prepared using suitablemethods, such as reverse proteolysis (Fisch et al., Bioconjugate Chem.,3:147-153 (1992); Werlen et al., Bioconjugate Chem., 5:411-417 (1994);Kumaran et al., Protein Sci. 6(10):2233-2241 (1997); Itoh et al.,Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al., Biotechnol.Bioeng., 56(4):456-463 (1997)), and the methods described in Hermanson,G. T., Bioconjugate Techniques, Academic Press: San Diego, Calif.(1996).

The method of the present invention also uses an anti-IL-23 antibodycomposition comprising at least one, at least two, at least three, atleast four, at least five, at least six or more anti-IL-23 antibodiesthereof, as described herein and/or as known in the art that areprovided in a non-naturally occurring composition, mixture or form. Suchcompositions comprise non-naturally occurring compositions comprising atleast one or two full length, C- and/or N-terminally deleted variants,domains, fragments, or specified variants, of the anti-IL-23 antibodyamino acid sequence selected from the group consisting of 70-100% of thecontiguous amino acids of the SEQ ID NOs above, or specified fragments,domains or variants thereof. Preferred anti-IL-23 antibody compositionsinclude at least one or two full length, fragments, domains or variantsas at least one CDR or LBP containing portions of the anti-IL-23antibody sequence described herein, for example, 70-100% of the SEQ IDNOs above, or specified fragments, domains or variants thereof. Furtherpreferred compositions comprise, for example, 40-99% of at least one of70-100% of the SEQ ID NOs above, etc., or specified fragments, domainsor variants thereof. Such composition percentages are by weight, volume,concentration, molarity, or molality as liquid or dry solutions,mixtures, suspension, emulsions, particles, powder, or colloids, asknown in the art or as described herein.

Antibody Compositions Comprising Further Therapeutically ActiveIngredients

The antibody compositions used in the method of the invention canoptionally further comprise an effective amount of at least one compoundor protein selected from at least one of an anti-infective drug, acardiovascular (CV) system drug, a central nervous system (CNS) drug, anautonomic nervous system (ANS) drug, a respiratory tract drug, agastrointestinal (GI) tract drug, a hormonal drug, a drug for fluid orelectrolyte balance, a hematologic drug, an antineoplastic, animmunomodulation drug, an ophthalmic, otic or nasal drug, a topicaldrug, a nutritional drug or the like. Such drugs are well known in theart, including formulations, indications, dosing and administration foreach presented herein (see, e.g., Nursing 2001 Handbook of Drugs,21^(st) edition, Springhouse Corp., Springhouse, Pa., 2001; HealthProfessional's Drug Guide 2001, ed., Shannon, Wilson, Stang,Prentice-Hall, Inc, Upper Saddle River, N.J.; Pharmcotherapy Handbook,Wells et al., ed., Appleton & Lange, Stamford, Conn., each entirelyincorporated herein by reference).

By way of example of the drugs that can be combined with the antibodiesfor the method of the present invention, the anti-infective drug can beat least one selected from amebicides or at least one antiprotozoals,anthelmintics, antifungals, antimalarials, antituberculotics or at leastone antileprotics, aminoglycosides, penicillins, cephalosporins,tetracyclines, sulfonamides, fluoroquinolones, antivirals, macrolideanti-infectives, and miscellaneous anti-infectives. The hormonal drugcan be at least one selected from corticosteroids, androgens or at leastone anabolic steroid, estrogen or at least one progestin, gonadotropin,antidiabetic drug or at least one glucagon, thyroid hormone, thyroidhormone antagonist, pituitary hormone, and parathyroid-like drug. The atleast one cephalosporin can be at least one selected from cefaclor,cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride,cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium,cefotaxime sodium, cefotetan disodium, cefoxitin sodium, cefpodoximeproxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime sodium,ceftriaxone sodium, cefuroxime axetil, cefuroxime sodium, cephalexinhydrochloride, cephalexin monohydrate, cephradine, and loracarbef.

The at least one coricosteroid can be at least one selected frombetamethasone, betamethasone acetate or betamethasone sodium phosphate,betamethasone sodium phosphate, cortisone acetate, dexamethasone,dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisoneacetate, hydrocortisone, hydrocortisone acetate, hydrocortisonecypionate, hydrocortisone sodium phosphate, hydrocortisone sodiumsuccinate, methylprednisolone, methylprednisolone acetate,methylprednisolone sodium succinate, prednisolone, prednisolone acetate,prednisolone sodium phosphate, prednisolone tebutate, prednisone,triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. Theat least one androgen or anabolic steroid can be at least one selectedfrom danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate,nandrolone phenpropionate, testosterone, testosterone cypionate,testosterone enanthate, testosterone propionate, and testosteronetransdermal system.

The at least one immunosuppressant can be at least one selected fromazathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immuneglobulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetilhydrochloride, sirolimus, and tacrolimus.

The at least one local anti-infective can be at least one selected fromacyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazolenitrate, clindamycin phosphate, clotrimazole, econazole nitrate,erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate,metronidazole (topical), miconazole nitrate, mupirocin, naftifinehydrochloride, neomycin sulfate, nitrofurazone, nystatin, silversulfadiazine, terbinafine hydrochloride, terconazole, tetracyclinehydrochloride, tioconazole, and tolnaftate. The at least one scabicideor pediculicide can be at least one selected from crotamiton, lindane,permethrin, and pyrethrins. The at least one topical corticosteroid canbe at least one selected from betamethasone dipropionate, betamethasonevalerate, clobetasol propionate, desonide, desoximetasone,dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate,fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasonepropionate, halcionide, hydrocortisone, hydrocortisone acetate,hydrocortisone butyrate, hydrocorisone valerate, mometasone furoate, andtriamcinolone acetonide. (See, e.g., pp. 1098-1136 of Nursing 2001 DrugHandbook.)

Anti-IL-23 antibody compositions can further comprise at least one ofany suitable and effective amount of a composition or pharmaceuticalcomposition comprising at least one anti-IL-23 antibody contacted oradministered to a cell, tissue, organ, animal or patient in need of suchmodulation, treatment or therapy, optionally further comprising at leastone selected from at least one TNF antagonist (e.g., but not limited toa TNF chemical or protein antagonist, TNF monoclonal or polyclonalantibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) orfragment, fusion polypeptides thereof, or a small molecule TNFantagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II),nerelimonmab, infliximab, eternacept, CDP-571, CDP-870, afelimomab,lenercept, and the like), an antirheumatic (e.g., methotrexate,auranofin, aurothioglucose, azathioprine, etanercept, gold sodiumthiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), animmunization, an immunoglobulin, an immunosuppressive (e.g.,basiliximab, cyclosporine, daclizumab), a cytokine or a cytokineantagonist. Non-limiting examples of such cytokines include, but are notlimited to, any of IL-1 to IL-23 et al. (e.g., IL-1, IL-2, etc.).Suitable dosages are well known in the art. See, e.g., Wells et al.,eds., Pharmacotherapy Handbook, 2^(nd) Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),each of which references are entirely incorporated herein by reference.

Anti-IL-23 antibody compounds, compositions or combinations used in themethod of the present invention can further comprise at least one of anysuitable auxiliary, such as, but not limited to, diluent, binder,stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvantor the like. Pharmaceutically acceptable auxiliaries are preferred.Non-limiting examples of, and methods of preparing such sterilesolutions are well known in the art, such as, but limited to, Gennaro,Ed., Remington's Pharmaceutical Sciences, 18^(th) Edition, MackPublishing Co. (Easton, Pa.) 1990. Pharmaceutically acceptable carrierscan be routinely selected that are suitable for the mode ofadministration, solubility and/or stability of the anti-IL-23 antibody,fragment or variant composition as well known in the art or as describedherein.

Pharmaceutical excipients and additives useful in the presentcomposition include, but are not limited to, proteins, peptides, aminoacids, lipids, and carbohydrates (e.g., sugars, includingmonosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatizedsugars, such as alditols, aldonic acids, esterified sugars and the like;and polysaccharides or sugar polymers), which can be present singly orin combination, comprising alone or in combination 1-99.99% by weight orvolume. Exemplary protein excipients include serum albumin, such ashuman serum albumin (HSA), recombinant human albumin (rHA), gelatin,casein, and the like. Representative amino acid/antibody components,which can also function in a buffering capacity, include alanine,glycine, arginine, betaine, histidine, glutamic acid, aspartic acid,cysteine, lysine, leucine, isoleucine, valine, methionine,phenylalanine, aspartame, and the like. One preferred amino acid isglycine.

Carbohydrate excipients suitable for use in the invention include, forexample, monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitolsorbitol (glucitol), myoinositol and the like. Preferred carbohydrateexcipients for use in the present invention are mannitol, trehalose, andraffinose.

Anti-IL-23 antibody compositions can also include a buffer or a pHadjusting agent; typically, the buffer is a salt prepared from anorganic acid or base. Representative buffers include organic acid salts,such as salts of citric acid, ascorbic acid, gluconic acid, carbonicacid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris,tromethamine hydrochloride, or phosphate buffers. Preferred buffers foruse in the present compositions are organic acid salts, such as citrate.

Additionally, anti-IL-23 antibody compositions can include polymericexcipients/additives, such as polyvinylpyrrolidones, ficolls (apolymeric sugar), dextrates (e.g., cyclodextrins, such as2-hydroxypropyl-β-cyclodextrin), polyethylene glycols, flavoring agents,antimicrobial agents, sweeteners, antioxidants, antistatic agents,surfactants (e.g., polysorbates, such as “TWEEN 20” and “TWEEN 80”),lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol),and chelating agents (e.g., EDTA).

These and additional known pharmaceutical excipients and/or additivessuitable for use in the anti-IL-23 antibody, portion or variantcompositions according to the invention are known in the art, e.g., aslisted in “Remington: The Science & Practice of Pharmacy,” 19^(th) ed.,Williams & Williams, (1995), and in the “Physician's Desk Reference,”52^(nd) ed., Medical Economics, Montvale, N.J. (1998), the disclosuresof which are entirely incorporated herein by reference. Preferredcarrier or excipient materials are carbohydrates (e.g., saccharides andalditols) and buffers (e.g., citrate) or polymeric agents. An exemplarycarrier molecule is the mucopolysaccharide, hyaluronic acid, which maybe useful for intraarticular delivery.

Formulations

As noted above, the invention provides for stable formulations, whichpreferably comprise a phosphate buffer with saline or a chosen salt, aswell as preserved solutions and formulations containing a preservativeas well as multi-use preserved formulations suitable for pharmaceuticalor veterinary use, comprising at least one anti-IL-23 antibody in apharmaceutically acceptable formulation. Preserved formulations containat least one known preservative or optionally selected from the groupconsisting of at least one phenol, m-cresol, p-cresol, o-cresol,chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol,formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate),alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkoniumchloride, benzethonium chloride, sodium dehydroacetate and thimerosal,or mixtures thereof in an aqueous diluent. Any suitable concentration ormixture can be used as known in the art, such as 0.001-5%, or any rangeor value therein, such as, but not limited to 0.001, 0.003, 0.005,0.009, 0.01, 0.02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any range orvalue therein. Non-limiting examples include, no preservative, 0.1-2%m-cresol (e.g., 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol(e.g., 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g.,0.005, 0.01), 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9,1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001, 0.002,0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5,0.75, 0.9, 1.0%), and the like.

As noted above, the method of the invention uses an article ofmanufacture, comprising packaging material and at least one vialcomprising a solution of at least one anti-IL-23 specific antibody withthe prescribed buffers and/or preservatives, optionally in an aqueousdiluent, wherein said packaging material comprises a label thatindicates that such solution can be held over a period of 1, 2, 3, 4, 5,6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or greater.The invention further uses an article of manufacture, comprisingpackaging material, a first vial comprising lyophilized anti-IL-23specific antibody, and a second vial comprising an aqueous diluent ofprescribed buffer or preservative, wherein said packaging materialcomprises a label that instructs a patient to reconstitute theanti-IL-23 specific antibody in the aqueous diluent to form a solutionthat can be held over a period of twenty-four hours or greater.

The anti-IL-23 specific antibody used in accordance with the presentinvention can be produced by recombinant means, including from mammaliancell or transgenic preparations, or can be purified from otherbiological sources, as described herein or as known in the art.

The range of the anti-IL-23 specific antibody includes amounts yieldingupon reconstitution, if in a wet/dry system, concentrations from about1.0 μg/ml to about 1000 mg/ml, although lower and higher concentrationsare operable and are dependent on the intended delivery vehicle, e.g.,solution formulations will differ from transdermal patch, pulmonary,transmucosal, or osmotic or micro pump methods.

Preferably, the aqueous diluent optionally further comprises apharmaceutically acceptable preservative. Preferred preservativesinclude those selected from the group consisting of phenol, m-cresol,p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl,ethyl, propyl, butyl and the like), benzalkonium chloride, benzethoniumchloride, sodium dehydroacetate and thimerosal, or mixtures thereof. Theconcentration of preservative used in the formulation is a concentrationsufficient to yield an anti-microbial effect. Such concentrations aredependent on the preservative selected and are readily determined by theskilled artisan.

Other excipients, e.g., isotonicity agents, buffers, antioxidants, andpreservative enhancers, can be optionally and preferably added to thediluent. An isotonicity agent, such as glycerin, is commonly used atknown concentrations. A physiologically tolerated buffer is preferablyadded to provide improved pH control. The formulations can cover a widerange of pHs, such as from about pH 4 to about pH 10, and preferredranges from about pH 5 to about pH 9, and a most preferred range ofabout 6.0 to about 8.0. Preferably, the formulations of the presentinvention have a pH between about 6.8 and about 7.8. Preferred buffersinclude phosphate buffers, most preferably, sodium phosphate,particularly, phosphate buffered saline (PBS).

Other additives, such as a pharmaceutically acceptable solubilizers likeTween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40(polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene(20) sorbitan monooleate), Pluronic F68 (polyoxyethylenepolyoxypropylene block copolymers), and PEG (polyethylene glycol) ornon-ionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or188, Pluronic® polyls, other block co-polymers, and chelators, such asEDTA and EGTA, can optionally be added to the formulations orcompositions to reduce aggregation. These additives are particularlyuseful if a pump or plastic container is used to administer theformulation. The presence of pharmaceutically acceptable surfactantmitigates the propensity for the protein to aggregate.

The formulations can be prepared by a process which comprises mixing atleast one anti-IL-23 specific antibody and a preservative selected fromthe group consisting of phenol, m-cresol, p-cresol, o-cresol,chlorocresol, benzyl alcohol, alkylparaben, (methyl, ethyl, propyl,butyl and the like), benzalkonium chloride, benzethonium chloride,sodium dehydroacetate and thimerosal or mixtures thereof in an aqueousdiluent. Mixing the at least one anti-IL-23 specific antibody andpreservative in an aqueous diluent is carried out using conventionaldissolution and mixing procedures. To prepare a suitable formulation,for example, a measured amount of at least one anti-IL-23 specificantibody in buffered solution is combined with the desired preservativein a buffered solution in quantities sufficient to provide the proteinand preservative at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The formulations can be provided to patients as clear solutions or asdual vials comprising a vial of lyophilized anti-IL-23 specific antibodythat is reconstituted with a second vial containing water, apreservative and/or excipients, preferably, a phosphate buffer and/orsaline and a chosen salt, in an aqueous diluent. Either a singlesolution vial or dual vial requiring reconstitution can be reusedmultiple times and can suffice for a single or multiple cycles ofpatient treatment and thus can provide a more convenient treatmentregimen than currently available.

The present articles of manufacture are useful for administration over aperiod ranging from immediate to twenty-four hours or greater.Accordingly, the presently claimed articles of manufacture offersignificant advantages to the patient. Formulations of the invention canoptionally be safely stored at temperatures of from about 2° C. to about40° C. and retain the biologically activity of the protein for extendedperiods of time, thus allowing a package label indicating that thesolution can be held and/or used over a period of 6, 12, 18, 24, 36, 48,72, or 96 hours or greater. If preserved diluent is used, such label caninclude use up to 1-12 months, one-half, one and a half, and/or twoyears.

The solutions of anti-IL-23 specific antibody can be prepared by aprocess that comprises mixing at least one antibody in an aqueousdiluent. Mixing is carried out using conventional dissolution and mixingprocedures. To prepare a suitable diluent, for example, a measuredamount of at least one antibody in water or buffer is combined inquantities sufficient to provide the protein and, optionally, apreservative or buffer at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The claimed products can be provided to patients as clear solutions oras dual vials comprising a vial of lyophilized at least one anti-IL-23specific antibody that is reconstituted with a second vial containingthe aqueous diluent. Either a single solution vial or dual vialrequiring reconstitution can be reused multiple times and can sufficefor a single or multiple cycles of patient treatment and thus provides amore convenient treatment regimen than currently available.

The claimed products can be provided indirectly to patients by providingto pharmacies, clinics, or other such institutions and facilities, clearsolutions or dual vials comprising a vial of lyophilized at least oneanti-IL-23 specific antibody that is reconstituted with a second vialcontaining the aqueous diluent. The clear solution in this case can beup to one liter or even larger in size, providing a large reservoir fromwhich smaller portions of the at least one antibody solution can beretrieved one or multiple times for transfer into smaller vials andprovided by the pharmacy or clinic to their customers and/or patients.

Recognized devices comprising single vial systems include pen-injectordevices for delivery of a solution, such as BD Pens, BD Autojector®,Humaject®, NovoPen®, B-D®Pen, AutoPen®, and OptiPen®, GenotropinPen®,Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®,Intraject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®,Smartject® e.g., as made or developed by Becton Dickensen (FranklinLakes, N.J., www.bectondickenson.com), Disetronic (Burgdorf,Switzerland, www.disetronic.com; Bioject, Portland, Oreg.(www.bioject.com); National Medical Products, Weston Medical(Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis,Minn., www.mediject.com), and similary suitable devices. Recognizeddevices comprising a dual vial system include those pen-injector systemsfor reconstituting a lyophilized drug in a cartridge for delivery of thereconstituted solution, such as the HumatroPen®. Examples of otherdevices suitable include pre-filled syringes, auto-injectors, needlefree injectors, and needle free IV infusion sets.

The products may include packaging material. The packaging materialprovides, in addition to the information required by the regulatoryagencies, the conditions under which the product can be used. Thepackaging material of the present invention provides instructions to thepatient, as applicable, to reconstitute the at least one anti-IL-23antibody in the aqueous diluent to form a solution and to use thesolution over a period of 2-24 hours or greater for the two vial,wet/dry, product. For the single vial, solution product, pre-filledsyringe or auto-injector, the label indicates that such solution can beused over a period of 2-24 hours or greater. The products are useful forhuman pharmaceutical product use.

The formulations used in the method of the present invention can beprepared by a process that comprises mixing an anti-IL-23 antibody and aselected buffer, preferably, a phosphate buffer containing saline or achosen salt. Mixing the anti-IL-23 antibody and buffer in an aqueousdiluent is carried out using conventional dissolution and mixingprocedures. To prepare a suitable formulation, for example, a measuredamount of at least one antibody in water or buffer is combined with thedesired buffering agent in water in quantities sufficient to provide theprotein and buffer at the desired concentrations. Variations of thisprocess would be recognized by one of ordinary skill in the art. Forexample, the order the components are added, whether additionaladditives are used, the temperature and pH at which the formulation isprepared, are all factors that can be optimized for the concentrationand means of administration used.

The method of the invention provides pharmaceutical compositionscomprising various formulations useful and acceptable for administrationto a human or animal patient. Such pharmaceutical compositions areprepared using water at “standard state” as the diluent and routinemethods well known to those of ordinary skill in the art. For example,buffering components such as histidine and histidine monohydrochloridehydrate, may be provided first followed by the addition of anappropriate, non-final volume of water diluent, sucrose and polysorbate80 at “standard state.” Isolated antibody may then be added. Last, thevolume of the pharmaceutical composition is adjusted to the desiredfinal volume under “standard state” conditions using water as thediluent. Those skilled in the art will recognize a number of othermethods suitable for the preparation of the pharmaceutical compositions.

The pharmaceutical compositions may be aqueous solutions or suspensionscomprising the indicated mass of each constituent per unit of watervolume or having an indicated pH at “standard state.” As used herein,the term “standard state” means a temperature of 25° C.+/−2° C. and apressure of 1 atmosphere. The term “standard state” is not used in theart to refer to a single art recognized set of temperatures or pressure,but is instead a reference state that specifies temperatures andpressure to be used to describe a solution or suspension with aparticular composition under the reference “standard state” conditions.This is because the volume of a solution is, in part, a function oftemperature and pressure. Those skilled in the art will recognize thatpharmaceutical compositions equivalent to those disclosed here can beproduced at other temperatures and pressures. Whether suchpharmaceutical compositions are equivalent to those disclosed hereshould be determined under the “standard state” conditions defined above(e.g. 25° C.+/−2° C. and a pressure of 1 atmosphere).

Importantly, such pharmaceutical compositions may contain componentmasses “about” a certain value (e.g. “about 0.53 mg L-histidine”) perunit volume of the pharmaceutical composition or have pH values about acertain value. A component mass present in a pharmaceutical compositionor pH value is “about” a given numerical value if the isolated antibodypresent in the pharmaceutical composition is able to bind a peptidechain while the isolated antibody is present in the pharmaceuticalcomposition or after the isolated antibody has been removed from thepharmaceutical composition (e.g., by dilution). Stated differently, avalue, such as a component mass value or pH value, is “about” a givennumerical value when the binding activity of the isolated antibody ismaintained and detectable after placing the isolated antibody in thepharmaceutical composition.

Competition binding analysis is performed to determine if the IL-23specific mAbs bind to similar or different epitopes and/or compete witheach other. Abs are individually coated on ELISA plates. Competing mAbsare added, followed by the addition of biotinylated hrIL-23. Forpositive control, the same mAb for coating may be used as the competingmAb (“self-competition”). IL-23 binding is detected using streptavidin.These results demonstrate whether the mAbs recognize similar orpartially overlapping epitopes on IL-23.

One aspect of the method of the invention administers to a patient apharmaceutical composition comprising

In one embodiment of the pharmaceutical compositions, the isolatedantibody concentration is from about 77 to about 104 mg per ml of thepharmaceutical composition. In another embodiment of the pharmaceuticalcompositions the pH is from about 5.5 to about 6.5.

The stable or preserved formulations can be provided to patients asclear solutions or as dual vials comprising a vial of lyophilized atleast one anti-IL-23 antibody that is reconstituted with a second vialcontaining a preservative or buffer and excipients in an aqueousdiluent. Either a single solution vial or dual vial requiringreconstitution can be reused multiple times and can suffice for a singleor multiple cycles of patient treatment and thus provides a moreconvenient treatment regimen than currently available.

Other formulations or methods of stabilizing the anti-IL-23 antibody mayresult in other than a clear solution of lyophilized powder comprisingthe antibody. Among non-clear solutions are formulations comprisingparticulate suspensions, said particulates being a compositioncontaining the anti-IL-23 antibody in a structure of variable dimensionand known variously as a microsphere, microparticle, nanoparticle,nanosphere, or liposome. Such relatively homogenous, essentiallyspherical, particulate formulations containing an active agent can beformed by contacting an aqueous phase containing the active agent and apolymer and a nonaqueous phase followed by evaporation of the nonaqueousphase to cause the coalescence of particles from the aqueous phase astaught in U.S. Pat. No. 4,589,330. Porous microparticles can be preparedusing a first phase containing active agent and a polymer dispersed in acontinuous solvent and removing said solvent from the suspension byfreeze-drying or dilution-extraction-precipitation as taught in U.S.Pat. No. 4,818,542. Preferred polymers for such preparations are naturalor synthetic copolymers or polymers selected from the group consistingof gleatin agar, starch, arabinogalactan, albumin, collagen,polyglycolic acid, polylactic aced, glycolide-L(−) lactidepoly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lactic acid),poly(epsilon-caprolactone-CO-glycolic acid), poly(β-hydroxy butyricacid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate),poly(hydroxyethyl methacrylate), polyamides, poly(amino acids),poly(2-hydroxyethyl DL-aspartamide), poly(ester urea),poly(L-phenylalanine/ethylene glycol/1,6-diisocyanatohexane) andpoly(methyl methacrylate). Particularly preferred polymers arepolyesters, such as polyglycolic acid, polylactic aced, glycolide-L(−)lactide poly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lacticacid), and poly(epsilon-caprolactone-CO-glycolic acid. Solvents usefulfor dissolving the polymer and/or the active include: water,hexafluoroisopropanol, methylenechloride, tetrahydrofuran, hexane,benzene, or hexafluoroacetone sesquihydrate. The process of dispersingthe active containing phase with a second phase may include pressureforcing said first phase through an orifice in a nozzle to affectdroplet formation.

Dry powder formulations may result from processes other thanlyophilization, such as by spray drying or solvent extraction byevaporation or by precipitation of a crystalline composition followed byone or more steps to remove aqueous or nonaqueous solvent. Preparationof a spray-dried antibody preparation is taught in U.S. Pat. No.6,019,968. The antibody-based dry powder compositions may be produced byspray drying solutions or slurries of the antibody and, optionally,excipients, in a solvent under conditions to provide a respirable drypowder. Solvents may include polar compounds, such as water and ethanol,which may be readily dried. Antibody stability may be enhanced byperforming the spray drying procedures in the absence of oxygen, such asunder a nitrogen blanket or by using nitrogen as the drying gas. Anotherrelatively dry formulation is a dispersion of a plurality of perforatedmicrostructures dispersed in a suspension medium that typicallycomprises a hydrofluoroalkane propellant as taught in WO 9916419. Thestabilized dispersions may be administered to the lung of a patientusing a metered dose inhaler. Equipment useful in the commercialmanufacture of spray dried medicaments are manufactured by Buchi Ltd. orNiro Corp.

An anti-IL-23 antibody in either the stable or preserved formulations orsolutions described herein, can be administered to a patient inaccordance with the present invention via a variety of delivery methodsincluding SC or IM injection; transdermal, pulmonary, transmucosal,implant, osmotic pump, cartridge, micro pump, or other means appreciatedby the skilled artisan, as well-known in the art.

Therapeutic Applications

The present invention also provides a method for modulating or treatingpsoriasis, in a cell, tissue, organ, animal, or patient, as known in theart or as described herein, using at least one IL-23 antibody of thepresent invention, e.g., administering or contacting the cell, tissue,organ, animal, or patient with a therapeutic effective amount of IL-23specific antibody.

Any method of the present invention can comprise administering aneffective amount of a composition or pharmaceutical compositioncomprising an anti-IL-23 antibody to a cell, tissue, organ, animal orpatient in need of such modulation, treatment or therapy. Such a methodcan optionally further comprise co-administration or combination therapyfor treating such diseases or disorders, wherein the administering ofsaid at least one anti-IL-23 antibody, specified portion or variantthereof, further comprises administering, before concurrently, and/orafter, at least one selected from at least one TNF antagonist (e.g., butnot limited to, a TNF chemical or protein antagonist, TNF monoclonal orpolyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70or p85) or fragment, fusion polypeptides thereof, or a small moleculeTNF antagonist, e.g., TNF binding protein I or II (TBP-1 or TBP-II),nerelimonmab, infliximab, eternacept (Enbrel™), adalimulab (Humira™),CDP-571, CDP-870, afelimomab, lenercept, and the like), an antirheumatic(e.g., methotrexate, auranofin, aurothioglucose, azathioprine, goldsodium thiomalate, hydroxychloroquine sulfate, leflunomide,sulfasalzine), a muscle relaxant, a narcotic, a non-steroidanti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative,a local anesthetic, a neuromuscular blocker, an antimicrobial (e.g.,aminoglycoside, an antifungal, an antiparasitic, an antiviral, acarbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin,a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic,a corticosteriod, an anabolic steroid, a diabetes related agent, amineral, a nutritional, a thyroid agent, a vitamin, a calcium relatedhormone, an antidiarrheal, an antitussive, an antiemetic, an antiulcer,a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), afilgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), animmunization, an immunoglobulin, an immunosuppressive (e.g.,basiliximab, cyclosporine, daclizumab), a growth hormone, a hormonereplacement drug, an estrogen receptor modulator, a mydriatic, acycloplegic, an alkylating agent, an antimetabolite, a mitoticinhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, anantipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, astimulant, donepezil, tacrine, an asthma medication, a beta agonist, aninhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn,an epinephrine or analog, dornase alpha (Pulmozyme), a cytokine or acytokine antagonist. Suitable dosages are well known in the art. See,e.g., Wells et al., eds., Pharmacotherapy Handbook, 2^(nd) Edition,Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, TarasconPocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, LomaLinda, Calif. (2000); Nursing 2001 Handbook of Drugs, 21^(st) edition,Springhouse Corp., Springhouse, Pa., 2001; Health Professional's DrugGuide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, UpperSaddle River, N.J., each of which references are entirely incorporatedherein by reference.

Therapeutic Treatments

Typically, treatment of psoriasis is affected by administering aneffective amount or dosage of an anti-IL-23 antibody composition thattotal, on average, a range from at least about 0.01 to 500 milligrams ofan anti-IL-23 antibody per kilogram of patient per dose, and,preferably, from at least about 0.1 to 100 milligrams antibody/kilogramof patient per single or multiple administration, depending upon thespecific activity of the active agent contained in the composition.Alternatively, the effective serum concentration can comprise 0.1-5000μg/ml serum concentration per single or multiple administrations.Suitable dosages are known to medical practitioners and will, of course,depend upon the particular disease state, specific activity of thecomposition being administered, and the particular patient undergoingtreatment. In some instances, to achieve the desired therapeutic amount,it can be necessary to provide for repeated administration, i.e.,repeated individual administrations of a particular monitored or metereddose, where the individual administrations are repeated until thedesired daily dose or effect is achieved.

Preferred doses can optionally include 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and/or 100-500mg/kg/administration, or any range, value or fraction thereof, or toachieve a serum concentration of 0.1, 0.5, 0.9, 1.0, 1.1, 1.2, 1.5, 1.9,2.0, 2.5, 2.9, 3.0, 3.5, 3.9, 4.0, 4.5, 4.9, 5.0, 5.5, 5.9, 6.0, 6.5,6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9, 10, 10.5, 10.9, 11,11.5, 11.9, 20, 12.5, 12.9, 13.0, 13.5, 13.9, 14.0, 14.5, 4.9, 5.0,5.5., 5.9, 6.0, 6.5, 6.9, 7.0, 7.5, 7.9, 8.0, 8.5, 8.9, 9.0, 9.5, 9.9,10, 10.5, 10.9, 11, 11.5, 11.9, 12, 12.5, 12.9, 13.0, 13.5, 13.9, 14,14.5, 15, 15.5, 15.9, 16, 16.5, 16.9, 17, 17.5, 17.9, 18, 18.5, 18.9,19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 100, 200, 300, 400,500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500,and/or 5000 μg/ml serum concentration per single or multipleadministration, or any range, value or fraction thereof.

Alternatively, the dosage administered can vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms, kind of concurrenttreatment, frequency of treatment, and the effect desired. Usually adosage of active ingredient can be about 0.1 to 100 milligrams perkilogram of body weight. Ordinarily 0.1 to 50, and, preferably, 0.1 to10 milligrams per kilogram per administration or in sustained releaseform is effective to obtain desired results.

As a non-limiting example, treatment of humans or animals can beprovided as a one-time or periodic dosage of at least one antibody ofthe present invention 0.1 to 100 mg/kg, such as 0.5, 0.9, 1.0, 1.1, 1.5,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100mg/kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or, alternatively oradditionally, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, or 52, or, alternatively or additionally, at least oneof 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 years, or any combination thereof, using single, infusion or repeateddoses.

Dosage forms (composition) suitable for internal administrationgenerally contain from about 0.001 milligram to about 500 milligrams ofactive ingredient per unit or container. In these pharmaceuticalcompositions the active ingredient will ordinarily be present in anamount of about 0.5-99.999% by weight based on the total weight of thecomposition.

For parenteral administration, the antibody can be formulated as asolution, suspension, emulsion, particle, powder, or lyophilized powderin association, or separately provided, with a pharmaceuticallyacceptable parenteral vehicle. Examples of such vehicles are water,saline, Ringer's solution, dextrose solution, and 1-10% human serumalbumin. Liposomes and nonaqueous vehicles, such as fixed oils, can alsobe used. The vehicle or lyophilized powder can contain additives thatmaintain isotonicity (e.g., sodium chloride, mannitol) and chemicalstability (e.g., buffers and preservatives). The formulation issterilized by known or suitable techniques.

Suitable pharmaceutical carriers are described in the most recentedition of Remington's Pharmaceutical Sciences, A. Osol, a standardreference text in this field.

Alternative Administration

Many known and developed modes can be used according to the presentinvention for administering pharmaceutically effective amounts of ananti-IL-23 antibody. While pulmonary administration is used in thefollowing description, other modes of administration can be usedaccording to the present invention with suitable results. IL-23 specificantibodies of the present invention can be delivered in a carrier, as asolution, emulsion, colloid, or suspension, or as a dry powder, usingany of a variety of devices and methods suitable for administration byinhalation or other modes described here within or known in the art.

Parenteral Formulations and Administration

Formulations for parenteral administration can contain as commonexcipients sterile water or saline, polyalkylene glycols, such aspolyethylene glycol, oils of vegetable origin, hydrogenated naphthalenesand the like. Aqueous or oily suspensions for injection can be preparedby using an appropriate emulsifier or humidifier and a suspending agent,according to known methods. Agents for injection can be a non-toxic,non-orally administrable diluting agent, such as aqueous solution, asterile injectable solution or suspension in a solvent. As the usablevehicle or solvent, water, Ringer's solution, isotonic saline, etc. areallowed; as an ordinary solvent or suspending solvent, sterileinvolatile oil can be used. For these purposes, any kind of involatileoil and fatty acid can be used, including natural or synthetic orsemisynthetic fatty oils or fatty acids; natural or synthetic orsemisynthtetic mono- or di- or tri-glycerides. Parental administrationis known in the art and includes, but is not limited to, conventionalmeans of injections, a gas pressured needle-less injection device asdescribed in U.S. Pat. No. 5,851,198, and a laser perforator device asdescribed in U.S. Pat. No. 5,839,446 entirely incorporated herein byreference.

Alternative Delivery

The invention further relates to the administration of an anti-IL-23antibody by parenteral, subcutaneous, intramuscular, intravenous,intrarticular, intrabronchial, intraabdominal, intracapsular,intracartilaginous, intracavitary, intracelial, intracerebellar,intracerebroventricular, intracolic, intracervical, intragastric,intrahepatic, intramyocardial, intraosteal, intrapelvic,intrapericardiac, intraperitoneal, intrapleural, intraprostatic,intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal,intrasynovial, intrathoracic, intrauterine, intravesical, intralesional,bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermalmeans. An anti-IL-23 antibody composition can be prepared for use forparenteral (subcutaneous, intramuscular or intravenous) or any otheradministration particularly in the form of liquid solutions orsuspensions; for use in vaginal or rectal administration particularly insemisolid forms, such as, but not limited to, creams and suppositories;for buccal, or sublingual administration, such as, but not limited to,in the form of tablets or capsules; or intranasally, such as, but notlimited to, the form of powders, nasal drops or aerosols or certainagents; or transdermally, such as not limited to a gel, ointment,lotion, suspension or patch delivery system with chemical enhancers suchas dimethyl sulfoxide to either modify the skin structure or to increasethe drug concentration in the transdermal patch (Junginger, et al. In“Drug Permeation Enhancement;” Hsieh, D. S., Eds., pp. 59-90 (MarcelDekker, Inc. New York 1994, entirely incorporated herein by reference),or with oxidizing agents that enable the application of formulationscontaining proteins and peptides onto the skin (WO 98/53847), orapplications of electric fields to create transient transport pathways,such as electroporation, or to increase the mobility of charged drugsthrough the skin, such as iontophoresis, or application of ultrasound,such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402) (the abovepublications and patents being entirely incorporated herein byreference).

Having generally described the invention, the same will be more readilyunderstood by reference to the following Examples, which are provided byway of illustration and are not intended as limiting. Further details ofthe invention are illustrated by the following non-limiting Examples.The disclosures of all citations in the specification are expresslyincorporated herein by reference.

Example 1

Comparison of the efficacy and safety of guselkumab (GUS) with theanti-TNFα antibody adalimumab (ADA) and placebo (PBO) in patientstreated through one year.

To confirm findings from earlier studies, two pivotal, phase III trialswere conducted: VOYAGE 1 and VOYAGE 2. Efficacy, safety, andpatient-reported outcome (PRO) findings from VOYAGE 1 are reported,which compared guselkumab with adalimumab, a widely used TNF-αinhibitor, and placebo in psoriasis patients treated continuously forone year. In addition, an additional trial, known as VOYAGE 2 (describedin Example 2) compared guselkumab with adalimumab and placebo inpsoriasis patients treated continuously for 24 weeks, and also includeda randomized withdrawal period beginning after 28 weeks of treatment.

VOYAGE 1 Materials/Methods Summary: VOYAGE 1 is a phase 3, randomized,double-blind, placebo- and active comparator-controlled trial. Eligiblepatients (age≥18 years) had plaque psoriasis for ≥6 months, anInvestigator's Global Assessment [IGA] score≥3, a Psoriasis Area andSeverity Index [PASI] score≥12, and body surface area involvement≥10%,and were candidates for systemic therapy or phototherapy. At baseline,837 patients were randomized to either PBO at weeks 0/4/12 then GUS 100mg at weeks 16/20, and q8wk through week 44 (n=174); GUS 100 mg at weeks0/4/12, and q8wk through week 44 (n=329); or ADA 80 mg at week 0, 40 mgat week 1, and 40 mg q2wk through week 47 (n=334). The co-primaryendpoints were the proportions of GUS vs PBO patients achievingcleared/minimal disease (IGA 0/1) and 90% improvement in PASI score(PASI 90) at week 16. Other endpoints included the proportions of GUS vsADA patients achieving IGA 0/1, IGA 0, PASI 90, and PASI 100 at weeks16/24/48, and a Dermatology Life Quality Index score of 0/1 (DLQI 0/1),indicating no impact of psoriasis on health-related quality of life, atweeks 24/48. Safety was monitored through week 48.

VOYAGE 1 Summary Results: Significantly higher (p<0.001) proportions ofpatients in the GUS vs PBO group achieved IGA 0/1 (85.1% vs 6.9%) andPASI 90 (73.3% vs 2.9%) at week 16. GUS was also superior to ADA basedon the proportions of patients achieving IGA 0/1 (85.1% vs 65.9%) andPASI 90 (73.3% vs 49.7%) at week 16 (p<0.001). Likewise, significantlyhigher (p<0.001) proportions of patients achieved responses to GUS vsADA, respectively, at week 24: IGA 0 (52.6% vs 29.3%), IGA 0/1 (84.2% vs61.7%), PASI 100 (44.4% vs 24.9%), and PASI 90 (80.2% vs 53.0%).Corresponding response rates at week 48 were: IGA 0 (50.5% vs 25.7%),IGA 0/1 (80.5% vs 55.4%), PASI 100 (47.4% vs 23.4%), and PASI 90 (76.3%vs 47.9%), all p<0.001. The proportion of patients with a DLQI score of0/1 among GUS vs ADA patients was 60.9% vs 39.5% at week 24 and 62.5% vs38.9% at week 48 (both p<0.001). Through week 48, adverse eventsoccurred in 73.9% and 74.5% of GUS and ADA patients, respectively;serious adverse event rates were also similar for the GUS and ADA groups(4.9% vs 4.5%). Serious infections occurred in two GUS patients andthree ADA patients. Two malignancies (prostate and breast) occurred inthe GUS group. One myocardial infarction occurred in each activetreatment group.

VOYAGE 1 Summary Conclusions: GUS was superior to ADA in treatingmoderate-to-severe psoriasis, and was well tolerated, through one yearof treatment.

Background: Guselkumab, an interleukin-23 (IL-23) blocker, was superiorto adalimumab in treating moderate-to-severe psoriasis in a phase IItrial.

Objectives: To compare efficacy and safety of guselkumab with adalimumaband placebo in psoriasis patients treated for one year.

Methods: Patients were randomized to guselkumab 100 mg at week 0/4/12,then q8wk (n=329); placebo at week 0/4/16 followed by guselkumab 100 mgat week 16/20, then q8wk (n=174); or adalimumab 80 mg at week 0, 40 mgat week 1, 40 mg q2wk (n=334). Physician-reported outcomes(Investigators Global Assessment [IGA], Psoriasis Area and SeverityIndex [PASI]), patient-reported outcomes (PROs; Dermatology Life QualityIndex [DLQI], Psoriasis Symptom and Sign Diary [PSSD]), and safety wereevaluated through week 48.

Results: Guselkumab was superior (p<0.001) to placebo at week 16 (85.1%vs. 6.9% [IGA0/1] and 73.3% vs. 2.9%, [PASI90]). Guselkumab was alsosuperior (p<0.001) vs. adalimumab for IGA0/1 and PASI90 at week 16(85.1% vs. 65.9%, 73.3% vs. 49.7%); week 24 (84.2% vs. 61.7%, 80.2% vs.53.0%); and week 48 (80.5% vs. 55.4%, 76.3% vs. 47.9%). Furthermore,guselkumab significantly improved PROs through week 48. Adverse eventrates were comparable between treatments through week 48.

Limitations: Analyses were limited to 48 weeks.

Conclusions: Guselkumab demonstrated superior efficacy compared withadalimumab and is well-tolerated in psoriasis patients through one year.

Materials and Methods

Patients

The trial enrolled patients aged ≥18 years with moderate-to-severeplaque psoriasis (i.e., Investigator's Global Assessment [IGA]≥3,Psoriasis Area and Severity Index [PAST]≥12, and body surface area [BSA]involvement≥10%) for at least 6 months who were candidates for systemictherapy or phototherapy. Patients were ineligible if they had a historyor current signs of severe, progressive, or uncontrolled medicalconditions or had current or history of malignancy within 5 years,except nonmelanoma skin cancer (NMSC). Patients with history or symptomsof active tuberculosis (TB) were excluded. Patients could notparticipate if they had received guselkumab or adalimumab previously;other anti-TNF-α therapy within 3 months; other treatment targetingIL-12/23, IL-17, or IL-23 within 6 months; or any systemicimmunosuppressants (e.g., methotrexate) or phototherapy within 4 weeks.

Study Design

VOYAGE 1 was a phase III, randomized, double-blind, placebo- and activecomparator-controlled trial conducted at 104 global sites (December2014-April 2016). The study comprised an active-comparator period whenguselkumab was compared with adalimumab (week 0-48) and aplacebo-controlled period (weeks 0-16), after which placebo patientscrossed over to receive guselkumab through week 48. Patients wererandomized at baseline in a 2:1:2 ratio to guselkumab 100 mg at weeks 0,4, 12, and every-8-weeks thereafter through week 44; placebo at weeks 0,4, 12 followed by guselkumab 100 mg at weeks 16, 20, and every-8-weeksthereafter through week 44; or adalimumab 80 mg at week 0, 40 mg at week1, and 40 mg every-2 weeks thereafter through week 47. To maintain theblind, matching placebos were utilized. An institutional review board orethics committee approved the study protocol at participating sites;patients provided written informed consent before study initiation.

Assessments

Efficacy was evaluated using the IGA, PASI, scalp-specific IGA (ss-IGA),fingernail Physician's Global Assessment (f-PGA), Nail Psoriasis Areaand Severity Index (NAPSI), and PGA of the hands/feet (hf-PGA).Patient-reported outcomes were assessed utilizing the Dermatology LifeQuality Index (DLQI) and Psoriasis Symptom and Sign Diary (PSSD). Safetymonitoring included collection of adverse events (AEs) and laboratorytesting.

Antibodies-to-guselkumab were detected using a highly sensitive anddrug-tolerent electrochemiluminescence immunoassay; the sensitivity was3.1 ng/mL in guselkumab-free serum and 15 ng/mL with serum guselkumabconcentrations up to 3.125 μg/mL, which exceeds mean trough serumguselkumab levels.

Statistical Analyses

Co-primary endpoints were the proportions of patients achieving an IGAscore of cleared or minimal disease (IGA 0/1) and 90% improvement inPASI response (PASI 90) at week 16 in the guselkumab group compared withplacebo. Major secondary endpoints were also measured. All randomizedpatients were included in the primary and selected secondary efficacyanalyses; data were analyzed by randomized treatment group. The primaryand major secondary analyses were tested in a fixed sequence to controlfor multiplicity.

The co-primary endpoints and binary major secondary endpoints wereanalyzed using a Cochran-Mantel-Haenszel (CMH) chi-square statisticaltest stratified by pooled investigator site. With a sample size ofapproximately 750 patients, the power to detect a significant differencewas >99% for both co-primary endpoints. Continuous response parameterswere compared using an analysis of variance model with pooledinvestigator site as a covariate. All statistical testing was performed2-sided (α=0.05).

Patients who discontinued study agent due to lack of efficacy or an AEof psoriasis worsening or who started a protocol-prohibited psoriasistreatment were considered inadequate responders for binary endpoints,and had baseline values carried over for continuous endpoints. Otherpatients with missing data were considered inadequate responders forbinary endpoints (inadequate responder imputation) and had lastobservation carried forward for continuous endpoints (and all PSSDendpoints).

Safety analyses included all patients who received at least oneadministration of study agent and were summarized by actual treatment.The proportion of patients with antibodies-to-guselkumab was summarizedfor those receiving at least one dose of the biologic.

Results

At baseline, 837 patients were randomized to placebo (n=174), guselkumab(n=329), or adalimumab (n=334). Overall, 6.9%, 8.5%, and 15.6% ofpatients discontinued treatment in the placebo, guselkumab, andadalimumab groups, respectively, through week 48. Demographic anddisease characteristics were comparable across treatment groups atbaseline).

Clinical Responses

Guselkumab was superior to both placebo and/or adalimumab with respectto co-primary endpoints and all major secondary endpoints (all p<0.001).Compared with placebo, significantly higher proportions of patients inthe guselkumab group achieved IGA 0/1 (6.9% vs. 85.1%) and PASI 90 (2.9%vs. 73.3%) at week 16. Additionally, the proportions achieving at least75% improvement in PASI (PAST 75) as well as IGA 0 and PASI 100 weresignificantly higher for guselkumab vs. placebo at week 16. Guselkumabwas superior to adalimumab as measured by the proportion of patientsachieving IGA 0/1 (85.1% vs. 65.9%), PASI 90 (73.3% vs. 49.7%), and PASI75 (91.2% vs. 73.1%) at week 16. Significantly better responses toguselkumab compared with adalimumab were maintained at week 24 (IGA 0[52.6% vs. 29.3%], IGA 0/1 [84.2% vs. 61.7%], and PASI 90 [80.2% vs.53.0%]) and week 48 (50.5% vs. 25.7%, 80.5% vs. 55.4%, and 76.3% vs.47.9%, respectively). Additionally, higher proportions of patientsreceiving guselkumab attained response in higher PASI categoriescompared with adalimumab at week 48. After initiating guselkumab at week16, patients in the placebo cross-over group achieved responses similarto those observed in the guselkumab group.

Regional Psoriasis Measures

Regional psoriasis was evaluated based on the ss-IGA, f-PGA, NAPSI, andhf-PGA assessments. The proportion of patients achieving ss-IGA 0/1(absent/very mild scalp psoriasis) in the guselkumab group wassignificantly higher compared with placebo (83.4% vs. 14.5%, p<0.001) atweek 16; significantly better responses to guselkumab vs. adalimumabwere observed at week 24 (p<0.001) and week 48 (p=0.045). The proportionof patients achieving f-PGA 0/1 (clear/minimal) and percent improvementin NAPSI were significantly higher for guselkumab vs. placebo at week 16(p<0.001). The f-PGA responses were comparable at week 24, thoughguselkumab was superior to adalimumab by week 48 (p=0.038). Mean percentimprovement in NAPSI with guselkumab was significantly higher than thatfor placebo at week 16 (p<0.001) and comparable between guselkumab andadalimumab at weeks 24 and 48. Finally, the proportion of patientsachieving hf-PGA 0/1 (clear/almost clear) was significantly higher forguselkumab vs. placebo at week 16, and responses to guselkumab weresuperior to adalimumab at weeks 24 and 48 (p<0.001).

Health-Related Quality of Life Measures

At week 16, the improvement from baseline in DLQI was significantlygreater in the guselkumab group compared with placebo (mean change, −0.6vs. −11.2), as were the proportions of patients achieving DLQI 0/1 (noimpact of psoriasis on HRQoL) (both p<0.001). At weeks 24 and 48, bothimprovements from baseline in DLQI and proportions of patients achievingDLQI 0/1 were significantly higher for guselkumab vs. adalimumab(p<0.001).

At week 16, the improvement from baseline in the PSSD symptom score wassignificantly greater for guselkumab vs. placebo (mean change, −3.0 vs.−41.9); mean changes in the PSSD sign score were similarly favorable forguselkumab (both p<0.001). Likewise, at weeks 24 and 48, mean changes inthe PSSD symptom and sign scores in the guselkumab group weresignificantly greater than those in the adalimumab group (p<0.001). Theproportions of patients achieving a PSSD symptom score=0 with guselkumaband adalimumab, respectively, were 36.3% and 21.6% at week 24, and thesignificantly better response to guselkumab was maintained at week 48(p<0.001). Similar results were observed for the proportions of patientsachieving a PSSD sign score=0 at weeks 24 and 48 (p<0.001).

Safety Outcomes

During the placebo-controlled period (weeks 0-16), the proportion ofpatients with at least one AE was comparable across treatment groups,and the most commonly reported events were nasopharyngitis and upperrespiratory tract infection in all three groups. Serious AEs (SAEs) andAEs leading to study agent discontinuation occurred infrequently and insimilar proportions of patients for each treatment. Rates of overallinfections and infections requiring antibiotic treatment were comparableacross treatment groups. Two patients in the adalimumab groupexperienced serious infections (both cellulitis). One NMSC (i.e., basalcell carcinoma [BCC]) was reported in the guselkumab group, and no othermalignancies occurred in any group. One myocardial infarction (i.e.,major adverse cardiovascular event [MACE]) occurred in each activetreatment group through week 16.

The types and patterns of AEs reported through week 48 were similar tothose reported during the placebo-controlled period. The proportions ofpatients with at least one AE, an AE leading to discontinuation, or anSAE were similar in the guselkumab and adalimumab groups. Between weeks16-48, serious infections were reported in two patients in theguselkumab group (i.e., cellulitis in one and thigh abscess withpost-operative wound infection in another) and two in the adalimumabgroup (i.e., one abdominal abscess and one staphylococcal pneumonia witha fatal outcome in the patient with abdominal wall cellulitis reportedearlier). Overall infections and infections requiring antibiotictreatment occurred at comparable rates across treatment groups. No AEsof active tuberculosis or opportunistic infection were reported duringthe study. Two additional NMSCs (i.e., one BCC each in the guselkumaband adalimumab groups) and two malignancies (i.e., prostate and breastin the guselkumab group) were reported through week 48. No additionalMACE occurred after week 16. A single suicide attempt was reported in anadalimumab patient. Incidence rates of candidiasis and neutropenia werelow and comparable between the guselkumab and placebo groups (data notshown), and no events of Crohn's disease were reported through week 48.

Through week 48, the proportion of patients with an ISR (2.2% vs. 9.0%)and the proportion of injections associated with ISRs (0.5% vs 1.2%)were lower for guselkumab compared with adalimumab; most ISRs wereconsidered mild. Laboratory abnormalities rates were low, and nobetween-group differences were noted (data not shown).Antibodies-to-guselkumab were detected in 26/492 patients (5.3%) throughweek 44; titers were generally low (81%≤1:320). No apparent associationwas observed between antibody development and either reduced efficacy orISR occurrence (data not shown).

Discussion

The findings in VOYAGE 1 study, together with the VOYAGE 2 resultsdescribed in Example 2 below, confirm that two injections of guselkumab100 mg (weeks 0 and 4) and every 8-week maintenance therapy effectivelytreats moderate-to-severe psoriasis. Guselkumab was superior to placeboby substantial margins at week 16 using two rigorous endpoints (IGA 0/1and PASI 90). The onset of action of guselkumab was rapid, withsignificant response evident as early as week 2 compared with placebo.Guselkumab was also superior to adalimumab, which is a widely used andvery effective subcutaneous TNF-α inhibitor, at the week-16 endpoints ofIGA 0/1, PASI 90, and PASI 75. Response rates continued to improve withguselkumab beyond week 16. At weeks 24 and 48, approximately half of allpatients in the guselkumab group achieved complete clearance (IGA 0),which is associated with optimal HRQoL for patients with psoriasis.Patient-reported outcome endpoints (PSSD and DLQI) based on totalchange, or indicating minimal/no impact on HRQoL or no symptoms or signsof psoriasis, demonstrated guselkumab responses that were superior toplacebo at week 16 and adalimumab at weeks 24 and 48.

This study assessed multiple areas of the body where psoriasis ischallenging to treat, and guselkumab was highly effective in all regionsbased on rigorous endpoints. Guselkumab was superior to placebo at week16 and to adalimumab at weeks 24/48, indicating complete or nearlycomplete clearance of scalp and hand/foot psoriasis in at least 75% ofguselkumab-treated patients. Based on both the proportion of patientswith clear/minimal fingernail psoriasis (f-PGA 0/1) and the mean percentimprovement in NAPSI, guselkumab was superior to placebo at week 16.Nail responses were comparable between active treatments at weeks 24 and48, and guselkumab was superior to adalimumab (75% vs. 62%) for f-PGA0/1 at week 48.

Rates and types of AEs, SAES, and laboratory abnormalities weregenerally comparable between the guselkumab and placebo groups throughweek 16 and between the guselkumab and adalimumab groups through week48. Rates of serious infections, malignancies, and MACE were low acrosstreatment groups. No notable differences in the incidence of neutropeniaor candidiasis, were observed between the guselkumab and control groups.No AEs of Crohn's disease occurred in any treatment group, and onesuicide attempt was reported in the adalimumab group. The number ofinjections and proportions of patients with ISRs were higher foradalimumab compared with guselkumab. The size and duration of this studymay not allow for assessment of uncommon events or those with a longlatency; however, longer-term treatment will be evaluated in ongoingstudy extensions.

VOYAGE 1 confirms the role of IL-23 in the pathogenesis of psoriasis.TNF-α inhibitors are effective in many diseases, and TNF-α is involvedin normal systemic inflammatory and immunologic processes. Selectivetargeting of the IL-23 pathway provides more psoriasis-specific cytokineinhibition with a higher degree of efficacy while maintaining afavorable safety profile, when compared with TNF-α blockade. IL-23 is akey driver of Th17 cell differentiation and survival and an upstreamregulator of IL-17A, a central pro-inflammatory effector cytokineimplicated in the pathogenesis of psoriasis. Moreover, IL-23 stimulatesthe production of other Th17 cytokines (e.g., IL-22) by other celltypes, including innate lymphoid cells type 3 (ILC3) cells and γδT-cells. Therefore, inhibition of IL-23 blocks downstream production ofIL-17A, IL-22, and other cell types. Since many IL-17A-producing cellsare dependent upon IL-23 for survival, inhibition of IL-23 may reducethe number of these pathogenic cells. This may explain the long durationof effect and allow for the convenient dosing interval of guselkumabcompared with both anti-TNF-α and anti-IL-17 agents.

The findings, together with those from VOYAGE 2, demonstrate thesuperior efficacy of guselkumab compared with adalimumab in psoriasis,efficacy in regional disease of the scalp, nails, and hands/feet, and apositive safety profile. The favorable safety profile through one yearis not unexpected, considering the reassuring long-term safety findingsreported for a related treatment, ustekinumab, which blocks both IL-12and IL-23. Study extensions will continue to examine the efficacy andsafety of guselkumab and add to the understanding of long-term IL-23blockade based on studies of ustekinumab.

Example 2 VOYAGE 2 Results

To confirm the therapeutic potential of guselkumab, the Phase 3 VOYAGE 1and VOYAGE 2 studies assessed the efficacy and safety of guselkumabversus placebo and adalimumab. VOYAGE 1 assessed continuous 1-yeartreatment, and VOYAGE 2 assessed continuous treatment for 24 weeks andalso evaluated the efficacy and safety of continuous maintenance therapybeyond 28 weeks of therapy using a randomized withdrawal approach.Additionally, VOYAGE 2 assessed the transition from adalimumab toguselkumab, providing clinically-relevant information about patients whoswitch biologics.

Materials and Methods

Patients

Adults (aged ≥18 years) with moderate-to-severe plaque-type psoriasiswere eligible. Major inclusion/exclusion criteria are summarized inVOYAGE 1 above. The study protocol was approved by an investigationalreview board at each site, and written informed consent was provided byall patients.

Study Design

VOYAGE 2 was a Phase 3, multicenter, randomized, double-blind, placebo-and adalimumab comparator-controlled study (NCT02207244) conducted in115 global sites between November 2014 and June 2016. The studyconsisted of a placebo-controlled period (weeks 0 to 16), an activecomparator-controlled period (weeks 0 to 28), and a randomizedwithdrawal and retreatment period (weeks 28 to 72). Study resultsthrough week 48 are presented here. Patients were randomized at baseline2:1:1 to guselkumab 100 mg at weeks 0, 4, 12, and 20; placebo at weeks0, 4, 12, then guselkumab at weeks 16 and 20; or adalimumab 80 mg atweek 0, 40 mg at week 1, and every-two-weeks (q2w) thereafter throughweek 23.

At week 28, guselkumab-treated patients achieving a 90% improvement frombaseline in Psoriasis Area and Severity Index (PASI 90; responders) werere-randomized in a 1:1 ratio to guselkumab or placebo. In this trial, aninadequate responder was defined as not achieving PASI90 from thetreatment. Upon loss of ≥50% of week-28 PASI response, patients wereretreated with guselkumab, another dose 4 weeks later, then q8wthereafter. Guselkumab nonresponders continued guselkumab treatment.Placebo→guselkumab nonresponders at week 28 continued guselkumab q8w,while responders received placebo q8w beginning at week 28. Upon loss of≥50% of week 28-PASI response, patients were retreated with guselkumab,followed by another dose 4 weeks later, then q8w thereafter. Adalimumabnonresponders initiated guselkumab at week 28, another dose 4 weekslater, then q8w thereafter. Adalimumab responders received placebo andupon loss of ≥50% of week 28-PASI response, initiated guselkumab,another dose 4 weeks later, then q8w thereafter. To maintain the blind,both guselkumab and adalimumab placebos were administered as necessary.

Efficacy and Safety Assessments

Efficacy was assessed through week 24 and safety through week 28. Keyefficacy, including general and regional psoriasis, patient-reportedoutcomes, and safety assessments are discussed in detail in the VOYAGE 1study. In addition, the Medical Outcomes Study 36-Item Short Form(SF-36) was evaluated in this study.

Study Endpoints

The co-primary endpoints were the proportions of patients achieving anIGA score of cleared (0) or minimal (1) at week 16 and the proportion ofpatients achieving a PASI 90 response at week 16, comparing theguselkumab and placebo groups. Major secondary endpoints were alsomeasured. Regional psoriasis endpoints evaluating the scalp,fingernails, and hand/feet were described in detail elsewhere.

Statistical Analysis

All randomized patients were included in the primary analysis and somesecondary efficacy analyses according to their assigned treatment group.To assess maintenance dosing versus treatment withdrawal for the majorsecondary endpoints, all patients who underwent the second randomizationand had PASI evaluation after week 28 were included in the analyses.

The co-primary endpoints and binary major secondary endpoints wereanalyzed using a two-sided Cochran-Mantel-Haenszel (CMH) chi-squaredstatistical test (α=0.05) stratified by investigator site. Continuousresponse parameters were compared using an analysis of variance modelwith site as a covariate. For the time to loss of PASI 90 response, thelog-rank test stratified by site was used.

Patients who discontinued study treatment due to lack of efficacy or anAE of worsening of psoriasis, or who started a protocol-prohibitedmedication/therapy that could improve psoriasis were consideredtreatment failures. Patients who met treatment failure criteria beforeweek 16 and patients not returning for week-16 evaluation wereconsidered nonresponders for the week-16 primary endpoint. For patientsrandomized to placebo, only those who crossed-over to receive guselkumabat/after week 16 were included in the efficacy analyses after week 16.

To control the overall Type 1 error rate, the primary analysis and majorsecondary analyses were tested in a fixed sequence, with the first majorsecondary endpoint being tested only if the co-primary endpoints weremet, and the subsequent endpoint(s) tested only if the precedingendpoint in the sequence were met.

Safety analyses included all patients who received at least one studyagent administration. Adverse events and serious adverse events (SAEs)were grouped according to the treatment received. Antibodies toguselkumab were analyzed.

Results

Patient Disposition and Baseline Demographic Characteristics

A total of 1279 patients were screened and 992 were randomized 2:1:1 toreceive guselkumab (n=496), placebo (n=248), or adalimumab (n=248) (FIG.2). Overall, 9.7% (96/992) of patients discontinued the study agentthrough week 48 (guselkumab: 7.9%; placebo: 11.7%; adalimumab: 11.3%).Baseline demographics and disease characteristics were generallycomparable among groups.

Efficacy

Guselkumab was superior to both placebo and/or adalimumab with respectto the co-primary endpoints and all major secondary endpoints (allp<0.001).

Placebo-Controlled Period (Weeks 0-16)

At week 16, significantly greater proportions of guselkumab patientsachieved an IGA of cleared (0) or minimal (1) compared with the placebopatients (84.1% vs. 8.5%; p<0.001), and achieved a PASI 90 response(70.0% vs. 2.4%; p<0.001) (co-primary endpoints). Significantly higherPASI percent improvement was observed as early as week 2 in guselkumabvs. placebo patients (p<0.001). Additionally, at week 16, significantlyhigher proportions of guselkumab patients achieved PASI 75 and PASI 100responses compared with placebo patients. Guselkumab patients achievedgreater improvement in all regional psoriasis outcome assessments,compared with placebo at week 16 including: ss-IGA, f-PGA, NAPSI, andhf-PGA. Similar to VOYAGE 1, guselkumab was superior to placebo at week16 in all patient-reported outcomes including Dermatology Life QualityIndex (DLQI) and Psoriasis Symptom and Sign Diary (PSSD), and inaddition, SF-36.

Active-Comparator Period (Weeks 0-24)

Significantly greater proportions of patients in the guselkumab groupachieved IGA 0/1, PASI 90, and PASI 75 responses at week 16. At week 24,significantly higher response rates were maintained in the guselkumabvs. adalimumab patients for IGA 0 (51.5% vs. 31.5%), IGA 0/1 (83.5% vs.64.9%), PASI 90 (75.2% vs. 54.8%), and PASI 100 (44.2% vs. 26.6%).Consistent with VOYAGE 1, greater improvements in regional psoriasisdisease scores were observed at week 24 in guselkumab patients comparedwith adalimumab patients, with the exception of f-PGA 0/1 and percentimprovement in NAPSI, which were comparable. At week 24, the proportionsof patients achieving DLQI 0/1, mean changes in the PSSD symptom andsign scores, proportions of patients achieving a PSSD symptom score of 0and a sign score of 0 were significantly greater in the guselkumab groupthan in the adalimumab group (p<0.001)

Randomized Withdrawal and Retreatment Period (Weeks 28-48)

PASI 90 responses were better maintained in guselkumab week-28responders continuing guselkumab (maintenance group) versus respondersre-randomized to placebo (withdrawal group). The median time to loss ofPASI 90 response was 15.2 weeks for patients randomized to thewithdrawal group. Among patients withdrawn from guselkumab at week 28,PASI 90 response rates began to diverge from the maintenance group atweek 32. Through week 48, 88.6% of the maintenance patients sustained aPASI 90 response versus 36.8% of withdrawal patients. In addition, atweek 48, clinical responses (IGA, PASI) were significantly greater inmaintenance group than withdrawal group (p<0.001). Improvements in DLQIand PSSD symptom or sign scores from baseline were also significantlygreater at week 48 in the maintenance vs. withdrawal groups (bothp<0.001). Through week 48, a small number of patients (n=16) wereretreated with guselkumab.

Switching Adalimumab Nonresponders to Guselkumab

Overall, 112 adalimumab nonresponders initiated guselkumab at week 28 (5weeks after the last adalimumab dose). In these patients, PASI 90(relative to baseline) and PASI 100 response rates increased afterswitching, reaching 66.1% and 28.6%, respectively at week 48.

Safety

Placebo-Controlled Period (Weeks 0-16)

The proportions of patients with at least one AE, AEs leading todiscontinuation, and SAEs were comparable between the guselkumab andplacebo groups. The most commonly reported events were nasopharyngitis,headache, and upper respiratory tract infection. Rates of infections,infections requiring treatment, and serious infections were similaramong groups. No malignancies or nonmelanoma skin cancers (NMSC) werereported through week 16. One major adverse cardiovascular event (MACE)(myocardial infarction [MI]) occurred in the adalimumab group. A higherproportion of adalimumab patients had injection site reactions (ISR)(6.9% vs 2.6%) and injections resulting in ISRs (1.5% vs. 0.9%) comparedwith guselkumab patients. All injection site reactions were mild.

Active-Comparator Period (Weeks 0-28)

The types of AEs were similar to those reported in theplacebo-controlled period. The proportions of patients with at least oneAE, AEs leading to discontinuation, and SAEs were comparable between theguselkumab and adalimumab groups. Infections and infections requiringtreatment were also comparable between guselkumab and adalimumab groups.Three serious infections each were reported in the guselkumab(bronchitis, erysipelas, and soft tissue infection) and adalimumabgroups (two cases of tuberculosis [one disseminated], and one injectionsite abscess). One malignancy (prostate cancer) and two NMSCs (onesquamous cell carcinoma [SCC] in the guselkumab group and one basal cellcarcinoma [BCC] in the placebo→guselkumab group) were reported. Two MACE(one MI each in guselkumab and adalimumab groups) were reported.

Randomized Withdrawal and Retreatment Period (Weeks 28-48)

From weeks 28-48, no patients discontinued due to AEs; one seriousinfection (appendicitis) was reported in the maintenance group. Noadditional malignancies, NMSC, or MACE were reported. No AEs werereported among the 16 retreated patents.

Additional Safety through Week 48

Through week 48, one additional BCC and one additional SCC of the skinoccurred in the placebo→guselkumab group (data not shown). Between weeks28-48, one additional MACE (MI) was reported in a placebo→guselkumabpatient. No events of serious infections, malignancies, or MACE occurredin the adalimumab→guselkumab group. No deaths, opportunistic infections,hypersensitivity, or anaphylactic reactions occurred through week 48.Rates of abnormal labs were low and comparable between the treatmentgroups through week 48. Antibodies to guselkumab were detected in 57/869patients (6.6%) through week 48; titers were generally low (88%≤1:160).No apparent associations were observed between antibody development anddecreased efficacy or ISR development (data not shown).

Discussion

VOYAGE 2 confirms the results of VOYAGE 1 demonstrating that guselkumabis highly effective in treating a broad moderate-to-severe psoriasispopulation. Guselkumab was superior to placebo at the week-16 co-primaryendpoints of IGA cleared/minimal and PASI 90 response. Guselkumab wasalso superior to adalimumab at the week-16 endpoints of IGAcleared/minimal, PASI 75/90, and by week 24, IGA cleared and PASI90/100. Guselkumab also successfully treated difficult regionalpsoriasis, including scalp, nails, and hands/feet. Investigator-assessedimprovements were mirrored by improvements in the patient-reportedoutcomes evaluated in VOYAGE 1, (DLQI and PSSD, a newly validatedinstrument that measures signs and symptoms of psoriasis). In addition,significant improvements in quality of life (QoL) (SF-36) were reportedin VOYAGE 2. The combined robust and comprehensive results from VOYAGE 1and VOYAGE 2 demonstrated superiority to both placebo and adalimumab.

Consistent with findings of other biologics for psoriasis, VOYAGE 2demonstrated that maintenance is superior to interrupted therapy, andthat blockade of IL-23 did not reverse the underlying mechanism ofpsoriasis. Unlike VOYAGE 1, in which patients continued treatment for 48weeks, in VOYAGE 2, PASI 90-responders were randomized at week 28 tocontinue guselkumab or receive placebo. Guselkumab-treated patientsmaintained response, including PASI 90, PASI 100, and IGA cleared, whilepsoriasis slowly recurred and QoL was reduced in placebo patients. Themedian time to loss of PASI 90 response for withdrawal patients was 15.2weeks, which is relevant because discontinuation rates are significantwith psoriasis biologics use through 1 year (often >50%).

Guselkumab was also effective in treating adalimumab nonresponders (didnot achieve PASI 90). Patients were classified asresponders/nonresponders at week 28, 5 weeks after the last adalimumabinjection. After 20 weeks of guselkumab treatment, ⅔ of the 112adalimumab nonresponders who switched to guselkumab achieved PASI 90(relative to baseline). Determining the rate at which patients who havehad sub-optimal responses achieve treatment goals could have asignificant impact on treatment decisions for those who seek greaterclearance, as more effective psoriasis therapies continue to enter themarket. While the mechanism of action of the broader efficacy ofguselkumab is unknown, in psoriasis, tumor necrosis factor-α (releasedfrom CD163+ macrophages/CD11c+ DCs) and IL-17A (released fromneutrophils, mast cells, and Th17 cells) are effector cytokinesprimarily acting on keratinocytes. IL-23 could be seen as theoverarching master cytokine for psoriasis because it drives theactivation of T cells and neutrophils, and induces IL-17 production.Moreover, IL-23 induces Th17 and other innate cells to produce IL-22,another cytokine implicated in psoriasis pathogenesis. Therefore,targeting the IL-23 pathway with an antibody such as guselkumab canprovide higher efficacy and durable responses.

The safety profile of guselkumab in this study was consistent withVOYAGE 1. The rates and types of AEs, SAES, and laboratory abnormalitieswere generally comparable to placebo though week 16 and adalimumabthrough week 28. Through week 48, rates of serious infections,malignancies, and MACE were low across treatment groups. Overall, therewere 2 cases of TB, both in adalimumab patients. There were 5malignancies in the guselkumab-treated patients, 4 of which were NMSCs(2 BCC and 2 SCC). ISRs occurred more frequently in adalimumab patients.While the safety profile of guselkumab is favorable, the size andduration of the study was inadequate to detect rare events.

There are several other limitations of VOYAGE 2. While comparison ofguselkumab to adalimumab in VOYAGE 2 was limited to 24 weeks, VOYAGE 1extended the comparison to adalimumab through 48 weeks. Moreimportantly, at week 48, few VOYAGE 2 patients withdrawn from activetherapy had lost adequate response to allow assessment of the efficacyand safety of retreatment. However, these numbers will be augmented at alater timepoint.

In conclusion, VOYAGE 2 confirms the results of VOYAGE 1 that guselkumabdemonstrated superior efficacy to adalimumab and comparable safety whenadministered in a convenient dosage regimen of a single 100-mg injectionat weeks 0, 4, and every-8-weeks. These results suggest that guselkumabmay be an important addition to psoriasis treatment alternatives.Additionally, VOYAGE 2 provides important data on the need forcontinuing therapy with guselkumab to maintain the highest level ofresponse, as well as successful transition from adalimumab toguselkumab.

ABBREVIATIONS AND ACRONYMS

AE adverse event

BCC basal cell carcinoma

BMI body mass index

BSA body surface area

DLQI Dermatology Life Quality Index

f-PGA Fingernail Physician's Global Assessment

hf-PGA Physician's Global Assessment of Hands and/or Feet

HRQoL health-related quality of life

IGA Investigator's Global Assessment

IL interleukin

NAPSI Nail Psoriasis Area and Severity Index

NMSC nonmelanoma skin cancer

PASI Psoriasis Area and Severity Index

PRO patient-reported outcome

PSSD Psoriasis Sign and Symptom Diary

SAE serious adverse event

ss-IGA Scalp-Specific Investigator's Global Assessment

TNFα-inhibitor tumor necrosis factor-α inhibitor

The efficacy observed in a Phase 2 trial of the anti-IL23 specificantibody guselkumab in patients with moderate-to-severe plaque psoriasisled to the hypothesis that guselkumab might be effective in patientswith an inadequate response to ustekinumab (an anti-IL-12/23p40 antibodyhaving the heavy chain CDR sequences of SEQ ID NOS:149-151, the lightchain CDR sequences of SEQ ID NOS:152-154, the heavy chain variableregion of SEQ ID NO:155 and the light chain variable region of SEQ IDNO:156). Therefore, in NAVIGATE, skin response rates in patients treatedwith guselkumab who previously had an inadequate response to ustekinumabevaluated. To rigorously answer this question, an enrichment studydesign with an open-label ustekinumab run-in followed by randomizationof primary nonresponders was employed.

Methods Summary: In this Phase 3, randomized, double-blind study, 871patients received open-label ustekinumab (45 mg or 90 mg) at weeks 0 and4. At week 16, 268 patients with an inadequate response to ustekinumab(Investigator's Global Assessment [IGA]≥2), patients that are notcleared nor almost cleared, were randomized (double-blind), toguselkumab 100 mg or continue ustekinumab; 585/871 (67%) patients withIGA 0/1 at week 16 continued open-label ustekinumab. The primaryendpoint was the number of visits at which randomized patients achievedan IGA 0/1 and ≥2 grade improvement (from week 16) from week 28 throughweek 40.Results Summary: The mean number of visits at which patients had an IGA0/1 and ≥2-grade improvement from week 28-40 was significantly greaterin the guselkumab group vs. the randomized ustekinumab group (1.5 vs.0.7; p<0.001). Proportions of patients with an IGA 0/1 and ≥2-gradeimprovement (from week 16), PASI75, PASI90, and PASI100 were greater inthe guselkumab group vs. the randomized ustekinumab group through week52. After week 16, 64.4% of patients in the guselkumab group and 55.6%in the randomized ustekinumab group had ≥1AE. Proportions of patientswith ≥1 serious AE (SAEs) were 6.7% (n=9) for guselkumab and 4.5% (n=6)for ustekinumab.Conclusions Summary: Ustekinumab-treated patients who have not achievedan IGA of “cleared” or “minimal” response by week 16 derived significantbenefit from switching to guselkumab.Background: Interleukin (IL)-23/IL-17 is the major pathway that drivesthe chronic inflammation underlying the pathophysiology of psoriasis.Ustekinumab is a monoclonal antibody targeting IL-12 and IL-23 and iscurrently approved for patients with plaque psoriasis. Guselkumab is anovel anti-interleukin-23 monoclonal antibody and has demonstrated highefficacy in patients with plaque psoriasis in two recent Phase 3 trials.

Patients and Methods

Patients. Adults (aged ≥18 years) were eligible if they had a diagnosisof moderate-to-severe plaque-type psoriasis for ≥6 months, a PsoriasisArea and Severity Index (PAST) score≥12, Investigator's GlobalAssessment (IGA) score≥3, body surface area (BSA) involvement≥10%, andwere candidates for phototherapy or systemic treatment for psoriasis.

Patients were ineligible if they had severe, progressive, oruncontrolled medical conditions or had a malignancy or history ofmalignancy within 5 years (exception of nonmelanoma skin cancer).Patients were excluded if they had a history or symptoms of active TB orif they tested positive for hepatitis B or seropositive for antibodiesto hepatitis C. Patients could not have received prior treatment withguselkumab or ustekinumab, therapeutic agents targeted to IL-12, IL-17,or IL-23 (other than guselkumab and ustekinumab) within 6 months offirst study agent administration, anti-TNF therapy (within 3 months orfive half-lives of first study agent administration), or any systemicimmunosuppressants or phototherapy (within 4 weeks of first study agentadministration).

Trial design. NAVIGATE was a phase 3, randomized, double-blind trialconducted between October 2014 and May 2016 at 100 sites in 10countries. The study contained a 16-week open-label period, a 28 weekrandomized active-treatment period, and 16-week follow-up period. Allpatients received open-label ustekinumab (patients weighing ≤100 kg: 45mg, patients weighing >100 kg: 90 mg) at weeks 0 and 4. At week 16,patients with an IGA≥2 (ie, inadequate response to ustekinumab) wererandomized to guselkumab 100 mg at weeks 16, 20, and every 8 weeks or tocontinue ustekinumab at week 16 and every 12 weeks. Randomization wasperformed using an interactive web response system with patientsstratified by baseline weight (≤100 kg vs >100 kg) and study site.Placebo injections were administered to maintain the blind. Patientswith an IGA of 0 or 1 continued receiving open label ustekinumab at week16 and every 12 weeks. Ustekinumab and guselkumab injections wereadministered through week 40 and week 44, respectively. Patients werefollowed for efficacy through week 52 and safety through week 60.

This study was conducted according to the principles in the Declarationof Helsinki and Good Clinical Practice. The protocol was approved by theInvestigational Review Board/Ethics Committee at each site. All patientsgave written informed consent before any study-related procedures wereperformed.

Trial assessments. Clinical efficacy was evaluated using the IGA(cleared [0], minimal [1], mild [2], moderate [3], or severe [4]) andPASI, (scale of 0-72; higher scores indicating more severe disease). Theprimary endpoint was the number of visits at which patients achieved anIGA score of cleared (0) or minimal (1) and ≥2-grade improvementrelative to week 16 from week 28 through week 40, among randomizedpatients (ie, those with an inadequate response [IGA≥2] to ustekinumabat week 16). Major secondary endpoints among randomized patients werethe number of visits at which patients achieved an IGA score of 0 fromweek 28 through week 40, the number of visits at which patients achieved≥90% improvement in PASI score (PASI90) from week 28 through week 40,and the proportion of patients achieving an IGA of 0/1 and ≥2-gradeimprovement relative to week 16 at week 28. Patient-reported outcomeassessments included the Dermatology Life Quality Index (DLQI), adermatology-specific instrument (scale 0-30) to assess overall qualityof life with higher scores indicating a greater effect of disease onquality of life, and the Psoriasis Symptoms and Signs Diary (PSSD), aself-administered questionnaire (0-10) measuring the severity ofpsoriasis symptoms (itch, pain, stinging, burning, and skin tightness)and signs (skin dryness, cracking, scaling, shedding or flaking,redness, and bleeding) over the previous 7 days with higher scoresindicating greater disease severity.

Patients were monitored for adverse events (AEs), vital signs, andclinical laboratory (chemistry and hematology) values, through week 60.

Statistical analyses. The primary and major secondary analyses wereperformed for week-16 randomized patients. Data were analyzed byrandomized treatment group. Patients who discontinued study treatmentdue to lack of efficacy or an AE of worsening of psoriasis, or whostarted a protocol-prohibited medication/therapy that could improvepsoriasis were considered nonresponders from that point afterward.Missing data for randomized patients were imputed as nonresponse forcategorical variables. The primary and major secondary endpoints in therandomized treatment groups were compared using theCochran-Mantel-Haenszel test stratified by baseline weight (≤100kg, >100 kg). The sample size (130 patients/treatment group) was chosento have approximately 98% power to detect the treatment differencebetween ustekinumab and guselkumab for the primary endpoint at asignificance level of 0.05 (2-sided).

Safety analyses included all patients who received ≥1 administration ofstudy agent, and AEs were summarized according to the actual treatmentreceived.

Results

Trial population. A total of 872 patients were enrolled, and 871received open-label ustekinumab. Baseline demographics and diseasecharacteristics were generally similar in the randomized treatmentgroups and the nonrandomized treatment group with the exception that ahigher proportion of patients in the randomized group received previousanti-TNF therapy (Table 1).

Eighteen (18) patients discontinued ustekinumab through week 16 (FIG.1). At week 16, 268 patients had an IGA score ≥2 and were randomized ina double-blinded fashion to guselkumab 100 mg (n=135) or ustekinumab(n=133); 585/871 (67.2%) patients had an IGA score of 0/1 and continuedopen-label ustekinumab (nonrandomized group). Among the randomizedpatients, 25 (guselkumab, n=9 [6.7%]; ustekinumab, n=20 [15.0%])discontinued the study agent from weeks 16-44. Seventeen (17) patients(2.9%) who continued open-label ustekinumab discontinued treatment fromweeks 16-40.

Clinical efficacy. During the open-label run-in, 68.5% (589/860) ofpatients achieved an IGA score of 0 or 1, 73.7% a PASI75, and 49.0% aPASI90 at week 16.

Among randomized patients, the guselkumab group had a significantlyhigher mean number of visits at which patients had an IGA score of 0 or1 and at least a 2-grade improvement relative to week 16 from week 28through week 40 (primary endpoint) compared to the ustekinumab group(1.5 vs. 0.7; p<0.001) (Table 2). All major secondary endpoints werealso met. The mean number of visits at which patients had a PASI90relative to baseline, between week 28 and week 40 was significantlyhigher in the guselkumab group than in the randomized ustekinumab group(2.2 vs 1.1; p<0.001). The mean number of visits at which patients hadan IGA score of 0 between week 28 and week 40 was significantly greaterfor patients in the guselkumab group compared with the randomizedustekinumab group (0.9 vs. 0.4; p<0.001). The proportion of patientswith an IGA score of 0 or 1 and ≥2-grade improvement relative to week 16at week 28 was significantly greater in the guselkumab group (31.1%)than in the randomized ustekinumab group (14.3%, p=0.001) (Table 2).

Among randomized patients, the proportions of patients with an IGA scoreof 0 or 1 and ≥2-grade improvement relative to week 16 and theproportions of patients achieving PASI75/90/100 responses, relative tobaseline, were consistently numerically greater in the guselkumab groupthan in the randomized ustekinumab group from week 20 through week 52(FIG. 2). Response rates increased in guselkumab-randomized patientsfrom week 16, reaching a maximum at week 36 (20 weekspost-randomization). Response rates in the randomized ustekinumab groupslightly increased from week 16, reaching a plateau at week 32 with aperiodic loss of response every 12 weeks. Responses in both groups weregenerally maintained through week 52 (FIG. 2). Separation of responsesbetween the groups occurred as early as week 20 (4 weekspost-randomization) and increased over time.

A total of 585 patients (67.2%) had an IGA score of 0 or 1 at week 16and continued open-label ustekinumab. At week 52, 81.1% of thesepatients maintained this response, with 42.6% having an IGA score of 0.Nearly all patients in the nonrandomized ustekinumab group had a PASI75at week 16, 69.7% had a PASI90, and 27.2% had a PASI100. These levelswere maintained through week 52.

Patient reported outcome assessments. At week 16, 131 patients in eachrandomized group had a DLQI score >1 (Table 2). Of these patients, asignificantly greater proportion of patients in the guselkumab group hada DLQI score of 0 or 1 at week 52 compared with the ustekinumab group(38.8% vs. 19.0%; p=0.002). Among randomized patients who had a PSSDsign score >0 or a PSSD symptom score >0 at week 16, significantlygreater proportions of guselkumab group patients had a PSSD sign scoreof 0 or a symptom score of 0, respectively, at week 52 compared with theustekinumab group (Table 2).

Adverse events in the open-label ustekinumab run-in group (week 0-week16). Among the 871 enrolled patients who received ≥1 administration ofustekinumab during the initial open-label period, 254 (29.2%)experienced ≥1 AE through week 16 (Table 3). The most common AEs werenasopharyngitis (5.4%) and upper respiratory infection (3.8%). Elevenpatients (1.3%) had ≥1 SAE. Two patients reported a serious infection(pneumonia and anal abscess). Malignancies occurred in two patients(basal cell carcinoma in both). No opportunistic infections or cases ofactive TB, major adverse cardiovascular events, or deaths occurredthrough week 16.

Adverse events in the randomized guselkumab and ustekinumab groups(weeks 16-60). In the two randomized groups, 64.4% of patients in theguselkumab group and 55.6% of patients in the ustekinumab group had atleast one AE from week 16 through week 60 (Table 3). Infections were themost common AEs in both randomized groups (guselkumab, 41.5%;ustekinumab 35.3%). The higher overall rate of AEs in the guselkumabgroup appeared to be related to a higher incidence of nasopharyngitisand upper respiratory tract infections. However, the proportion ofinfections requiring oral or parenteral antibiotic therapy was similarbetween the randomized groups (guselkumab: 15.6%; ustekinumab: 9.8%).

In the randomized groups, SAES were reported in nine (6.7%)guselkumab-treated patients and six (4.5%) ustekinumab-treated patients(Table 3). One serious infection occurred (septic arthritis in theguselkumab group). No opportunistic infections or cases of active TBwere reported. Two malignancies were reported (transitional cellcarcinoma of the bladder and squamous cell carcinoma of the neck, originunknown, in the guselkumab group). Three patients had a myocardialinfarction (guselkumab group: one female, aged 70 years and one male,aged 53 years; ustekinumab-group: one male, aged 66 years); all threepatients had at least two known cardiovascular risk factors. No deathsoccurred. Injection site reactions were uncommon between week 16 andweek 40; none severe. There were no anaphylactic or serum sickness-likereactions or AEs of Crohn's disease.

Adverse events in the open-label ustekinumab continuation group (weeks16-60). The most common AEs in the nonrandomized ustekinumab group werenasopharyngitis and upper respiratory tract infections (Table 3).

Twenty patients (3.4%) had ≥1 SAE from weeks 16-60. Five patients inthis group had a serious infection after week 16 (appendicitis,epididymitis, periodontitis paraspinal abscess, each occurring in onepatient; salpingitis and urinary tract infection, both occurred in thesame patient); there were no opportunistic infections or cases of activeTB. Four malignancies occurred: bile duct cancer, fatal metastaticpancreatic carcinoma, basal cell carcinoma, and squamous cell carcinomaof the skin. One patient had an acute myocardial infarction; the patienthad a history of multiple known risk factors. One death occurred (thepreviously mentioned patient with metastatic pancreatic carcinoma). Theincidence of injection site reactions was low (0.3%), and none weresevere. There were no anaphylactic or serum sickness-like reactions orAEs of Crohn's disease.

Discussion

This controlled Phase 3 study validates that guselkumab is effective intreating moderate-to-severe psoriasis patients who did not achieveoptimum clinical efficacy with ustekinumab. While ustekinumab is veryeffective in treating moderate-to-severe psoriasis, as with anytherapeutic agent, not all patients reach clear or almost completeclearance of their psoriasis. Recent studies established thatguselkumab, a monoclonal antibody that selectively targets IL-23, hadsubstantial efficacy in adults with moderate-to-severe psoriasis, andmay be more effective compared with ustekinumab. The results describedherein demonstrated that when ustekinumab inadequate-responders wererandomized to guselkumab vs continuing ustekinumab, guselkumab wassuperior to ustekinumab across all endpoints measured, including themean number of visits between week 28 and 40 at which patients had anIGA 0/1 and ≥2-grade improvement relative to week 16, an IGA score ofcleared and a PASI90 response. Over time, guselkumab was also superiorin the proportions of patients achieving clinical efficacy andpatient-reported outcome endpoints from weeks 16-52. The results aresignificant considering that this population had an inadequate responseto a highly efficacious therapy, ustekinumab, and provide dermatologistswith an approach to switching from ustekinumab to guselkumab.

In order to rigorously demonstrate the superiority of guselkumab inSTELARA inadequate responders, an enrichment design for ustekinumabinadequate-responders was employed, a more robust method than medicalhistory to establish inadequate responders, and used rigorous endpoints.Randomization of patients to either continue ustekinumab or initiateguselkumab was necessary since ustekinumab inadequate responders alsocontinued to improve after week 16. The ustekinumab dose regimenevaluated in NAVIGATE were consistent with the approved dosing regimenin most regions worldwide; thus dose escalation was not permitted. Thestudy utilized a relatively high level of efficacy to define ustekinumabresponders (IGA0/1, cleared or almost clear), consistent with patients'desires for higher efficacy. Two types of endpoints were employed: thenumber of visits at which patients obtained a high degree of responseand the proportion of patients achieving high levels of PASI and IGAresponse over time. The former assessed consistency of response at allvisits and helps address the differing peak and trough concentrations ofthe two biologics resulting from their respective administrationregimens; the latter endpoints, proportions of patients with IGA andPASI response at specific visits, are more intuitive and easilyinterpreted.

Regardless of the endpoints used, the number of visits at which responsewas achieved or the proportion of patients who achieved response overtime, the outcome consistently showed higher efficacy for guselkumab. Inthe randomized groups, PASI75/90/100 response rates were greater in theguselkumab group, with separation between the groups observed at week 20(4 weeks after the first guselkumab administration); response ratespeaked between weeks 32-36 and were generally maintained through week52. Responses were high, considering a patient population with aninadequate response to an effective drug like ustekinumab, with 50% ofguselkumab patients reaching PASI90 at week 52 compared with 24% ofustekinumab patients. Initial response with ustekinumab was consistentwith previous trials and response was generally maintained during theopen-label treatment period.

The safety profiles of guselkumab and ustekinumab were consistent withprevious studies. During the randomized-controlled period, the incidenceof AEs was slightly higher in the guselkumab group compared with therandomized ustekinumab group, primarily due to higher rates ofnasopharyngitis and upper respiratory tract infections. No seriousinfections, hypersensitivity reactions, or AEs of Crohn's diseaseoccurred in these groups, and the incidence of infections requiring oralor parenteral antibiotics was similar in the randomized groups. Fewguselkumab-treated patients had an injection-site-reaction, and all wereconsidered mild. There were no signals with regard to SAEs orhypersensitivity reactions when transitioning from ustekinumab toguselkumab, despite employing a guselkumab loading dose. The favorablesafety profile of guselkumab is not surprising considering the positivehistorical safety profile of ustekinumab and the narrower MOA ofguselkumab compared with ustekinumab.

The increased efficacy of guselkumab compared with ustekinumab inustekinumab inadequate responders further confirms the central role ofIL-23 in the pathogenesis of psoriasis, and suggests that activation ofthe proinflammatory Th1 pathway by interleukin-12 may not be as criticalto psoriasis immunopathogenesis as had been previously thought.Potential reasons for the increased efficacy of guselkumab compared withustekinumab may include more potent blockade of IL-23, more frequent andhigher dosing of guselkumab, and/or enhanced Th17 responses in thesetting of inhibition of IL-12.

Despite the rigorous design of the study, there are several limitations.The primary endpoint of this trial does not intuitively translate intoclinical response; however, it is supplemented by response rates usingIGA and PASI, (standard assessments in dermatology trials). In addition,the primary endpoint covered a limited time period from week 28 to week40.

In conclusion, it was demonstrated in a controlled enrichment designstudy that switching to guselkumab is an effective strategy in patientswho fail to achieve a high (or adequate) response with ustekinumab andthe transition is not associated with additional safety concerns.

TABLE 1 Patient demographics and disease characteristics at baseline.All patients Nonrandomized Open-label Open-label Patients randomizedUstekinumab Ustekinumab at week 16 Run-in Continuation GuselkumabUstekinumab Patients, n 871 585 135 133 Demographics Age (years) Mean ±SD 43.1 ± 13.2 42.9 ± 13.1 44.2 ± 13.4 43.0 ± 13.7 Sex, n (%) Male 566(65.0) 372 (63.6) 94 (70.4) 88 (66.2) Race, n (%) White 747 (85.8) 523(89.4) 109 (80.7) 99 (74.4) Asian 103 (11.8) 52 (8.9) 22 (16.3) 27(20.3) Other 21 (2.4) 10 (1.7) 4 7 Weight (kg) Mean ± SD 88.3 ± 22.086.8 ± 20.6 90.3 ± 22.2 91.3 ± 25.8 >100 kg 231 (26.5) 149 (25.5) 37(27.4) 37 (27.8) 1.1:10 kg 640 (73.5) 436 (74.5) 98 (72.6) 96 (72.2) BMI(kg/m2) Mean ± SD 29.7 ± 7.0  29.1 ± 6.4  30.3 ± 7.2  31.0 ± 8.6 Disease Characteristics Psoriasis disease duration Mean ± SD 16.8 ± 12.216.7 ± 12.3 18.2 ± 12.7 15.6 ± 10.9 Psoriatic arthritis Yes 128 (14.7)77 (13.2) 28 (20.7) 21 (15.8) BSA, % Mean ± SD 28.2 ± 16.8 26.8 ± 15.631.5 ± 19.8 30.5 ± 17.9 IGA Score Mild (2) 1 (0.1) 0 0 0 Moderate (3)694 (79.7) 477 (81.5) 103 (76.3) 100 (75.2) Severe (4) 176 (20.2) 108(18.5) 32 (23.7) 33 (24.8) PASI Score (0-72) Mean ± SD 21.6 ± 9.2  21.1± 9.2  22.6 ± 9.3  22.8 ± 9.4  DLQI (0-30) Mean ± SD 14.5 ± 7.2  14.2 ±7.1  15.5 ± 7.9  14.4 ± 6.7  PSSD Sign Score (0-100) n 866 584 133 132Mean ± SD 60.7 ± 20.4 58.8 ± 20.1 64.9 ± 20.3 63.7 ± 20.8 PSSD SymptomScore (0-100) n 866 584 133 132 Mean ± SD 50.6 ± 24.7 48.7 ± 24.0 55.7 ±25.5 52.9 ± 25.6 Previous treatment Topical agents 834 (95.8) 562 (96.1)128 (94.8) 126 (94.7) Phototherapy (PUVA or UVB) 446 (51.3) 287 (49.1)70 (51.9) 74 (55.6) Nonbiologic systemics (PUVA, MTX, 467 (53.6) 302(51.6) 80 (59.3) 73 (54.9) cyclosporine, acitretin, apremilast,tofacitinib) Anti-TNF agents (etanercept, 125 (14.4) 63 (10.8) 32 (23.7)26 (19.5) infliximab, adalimumab) Patients who had an contraindication,60 (48.0) 25 (39.7) 18 (56.3) 16 (61.5) had an inadequate response, orwere intolerant to ≥1 therapy Data reported as mean ± SD or n (%) unlessotherwise noted. BMI, body mass index; BSA, body surface area affectedby psoriasis; DLQI, Dermatology Life Quality Index; IGA, Investigator'sGlobal Assessment; PASI, Psoriasis Area and Severity Index; MTX,methotrexate; PSSD, Psoriasis Symptom and Sign Diary; PUVA, psoralen andultraviolet A radiation; TNF, tumor necrosis factor

TABLE 2 Clinical efficacy and patient-reported outcomes in therandomized treatment groups. Randomized Patients Guselkumab Ustekinumab(n = 135) (n = 133) Clinical Efficacy Number of visits^(‡) at whichpatients  1.5 ± 1.6* 0.7 ± 1.3 achieved IGA 0/1 and ≥2-grade improvement(relative to week 16) from week 28 through week 40 Proportion ofpatients with IGA 0/1 42 (31.1)* 19 (14.3) and ≥2-grade improvement(relative to week 16) at week 28 Number of visits^(‡) at which patients 0.9 ± 1.3* 0.4 ± 1.1 achieved IGA 0 from week 28 through week 40 Numberof visits^(‡) at which patients 2.2 (1.7)* 1.1 (1.5) achieved PAST 90from week 28 through week 40 Proportion of patients with PAST 65 (48.1)*30 (22.6) 90 response at week 28^(†) Patient-reported Outcomes Patientswith DLQI >1 at week 16, n 103 105 Patients with DLQI 0/1 at week52^(†), 40 (38.8)** 20 (19.0) n(%) Patients with PSSD sign score >0 at133 130 week 16, n Patients with a PSSD sign score of 0 12 (9.0)*** 4(3.1) at week 52, n (%) Patients with PSSD symptom score 123 126 >0 atweek 16, n Patients with a PSSD symptom score 25 (20.3)*** 12 (9.5) of 0at week 52, n (%) *p ≤ 0.001 **p < 0.01 ***p < 0.05 Data presented as n(%) or mean ± standard deviation. ^(‡)Maximum number of visits from week28 through week 40 = 4. ^(†)Nominal p value reported. DLQI, DermatologyLife Quality Index; IGA, Investigator's Global Assessment; PAST,Psoriasis Area and Severity Index; PSSD, Psoriasis Symptom and SignDiary

TABLE 3 Adverse events through week 60. Week 0-16 Nonrandomized PatientsOpen-label Open-label Week 16-60 Ustekinumab Ustekinumab RandomizedPatients Run-in Continuation Guselkumab Ustekinumab Patients, n 871 585135 133 Patients who discontinued 2 (0.2) 7 (1.2) 3 (2.2) 2 (1.5) due toAEs Patients with ≥1 AE 254 (29.2) 242 (41.4) 87 (64.4) 74 (55.6)Infections 142 (16.3) 121 (20.7) 56 (41.5) 47 (35.3) Infectionsrequiring oral 52 (6.0) 48 (8.2) 21 (15.6) 13 (9.8) or parenteralantibiotics Common AEs Nasopharyngitis 47 (5.4) 33 (5.6) 23 (17.0) 23(17.3) Upper respiratory tract 33 (3.8) 27 (4.6) 15 (11.1) 11 (8.3)infection Total injections, n 1737 1734 651 373 Injections with an 5(0.3) 2 (0.1) 7 (1.1) 0 injection site reaction Patients with ≥1 SAE 11(1.3) 20 (3.4) 9 (6.7) 6 (4.5) Serious infection 2 (0.2) 5 (0.9) 1 (0.7)0 Malignancies 2 (0.2) 4 (0.7) 2 (1.5) 0 Nonmelanoma skin 2 2 1 0 cancerMalignancy other than 0 2 1 0 NMSC MACE* 0 1 (0.2) 2 (1.5) 1 (0.8) Datapresented as n (%) unless otherwise noted. *Defined as myocardialinfarction, stroke, or cardiovascular death. AEs, adverse events; MACE,major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; SAE,serious adverse event

What is claimed is:
 1. A method of treating psoriasis in a patienttreated with an antibody to IL-12/23p40 and determined to be aninadequate responder to the IL-12/23p40 antibody treatment, comprising:administering to the patient determined to be an inadequate responder tothe IL-12/23p40 antibody treatment, an anti-IL-23 specific antibody in asafe and effective amount at a dose of 100 mg administered in an initialdose, 4 weeks after the initial dose and every 8 weeks after the dose at4 weeks, wherein the anti-IL-23 specific antibody comprises a lightchain variable region comprising the amino acid sequence of SEQ ID NO:116 and a heavy chain variable region comprising the amino acid sequenceof SEQ ID NO: 106, and is in a pharmaceutical composition consisting of100 mg/mL of the anti-IL-23 specific antibody; 7.9% (w/v) sucrose; 4.0mM Histidine; 6.9 mM L-Histidine monohydrochloride monohydrate; 0.053%(w/v) Polysorbate 80; and water as a diluent.